Derivatives And Methods Of Treating Hepatitis B Infections

ABSTRACT

Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/097,835, filed Dec. 30, 2014, and U.S. Provisional Application No.62/163,150, filed May 18, 2015. The contents of these provisionalapplications are incorporated herein by reference in their entirety.

BACKGROUND

Chronic hepatitis B virus (HBV) infection is a significant global healthproblem, affecting over 5% of the world population (over 350 millionpeople worldwide and 1.25 million individuals in the U.S.).

Despite the availability of a prophylactic HBV vaccine, the burden ofchronic HBV infection continues to be a significant unmet worldwidemedical problem, due to suboptimal treatment options and sustained ratesof new infections in most parts of the developing world. Currenttreatments do not provide a cure and are limited to only two classes ofagents (interferon alpha and nucleoside analogues/inhibitors of theviral polymerase); drug resistance, low efficacy, and tolerabilityissues limit their impact. The low cure rates of HBV are attributed atleast in part to the fact that complete suppression of virus productionis difficult to achieve with a single antiviral agent. However,persistent suppression of HBV DNA slows liver disease progression andhelps to prevent hepatocellular carcinoma. Current therapy goals forHBV-infected patients are directed to reducing serum HBV DNA to low orundetectable levels, and to ultimately reducing or preventing thedevelopment of cirrhosis and hepatocellular carcinoma.

There is a need in the art for therapeutic agents that can increase thesuppression of virus production and that can treat, ameliorate, and/orprevent HBV infection. Administration of such therapeutic agents to anHBV infected patient, either as monotherapy or in combination with otherHBV treatments or ancillary treatments, will lead to significantlyreduced virus burden, improved prognosis, diminished progression of thedisease and enhanced seroconversion rates.

SUMMARY

Provided herein are compounds useful for the treatment of HBV infectionin a subject in need thereof, having the structure:

or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula I is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I is a compound ofFormula III:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I is a compound ofFormula IV:

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein are pharmaceutical compositionscomprising a compound of Formula I, II, III, or IV, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier.

In one aspect, provided herein is a method of treating an HBV infectionin an individual in need thereof, comprising administering to theindividual a therapeutically effective amount of a compound of FormulaI, II, III, or IV, or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of eradicating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound ofFormula I, II, III, or IV, or a pharmaceutically acceptable saltthereof.

In another aspect, provided herein is a method of reducing the viralload associated with an HBV infection in an individual in need thereof,comprising administering to the individual a therapeutically effectiveamount of a compound of Formula I, II, III, or IV, or a pharmaceuticallyacceptable salt thereof.

In another aspect, provided herein is a method of reducing reoccurrenceof an HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of Formula I, II, III, or IV, or a pharmaceutically acceptablesalt thereof.

In another aspect, provided herein is a method of inhibiting or reducingthe formation or presence of HBV DNA-containing particles or HBVRNA-containing particles in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of Formula I, II, III, or IV, or a pharmaceutically acceptablesalt thereof.

In another aspect, provided herein is a method of reducing an adversephysiological impact of an HBV infection in an individual in needthereof, comprising administering to the individual a therapeuticallyeffective amount of a compound of Formula I, II, III, or IV, or apharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of inducing remission ofhepatic injury from an HBV infection in an individual in need thereof,comprising administering to the individual a therapeutically effectiveamount of a compound of Formula I, II, III, or IV, or a pharmaceuticallyacceptable salt thereof.

In another aspect, provided herein is a method of reducing thephysiological impact of long-term antiviral therapy for HBV infection inan individual in need thereof, comprising administering to theindividual a therapeutically effective amount of a compound of FormulaI, II, III, or IV, or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of prophylacticallytreating an HBV infection in an individual in need thereof, wherein theindividual is afflicted with a latent HBV infection, comprisingadministering to the individual a therapeutically effective amount of acompound of Formula I, II, III, or IV, or a pharmaceutically acceptablesalt thereof.

In an embodiment, the methods provided herein can further compriseadministering to the individual at least one additional therapeuticagent selected from the group consisting of an HBV polymerase inhibitor,immunomodulatory agents, pegylated interferon, viral entry inhibitor,viral maturation inhibitor, literature-described capsid assemblymodulator, reverse transcriptase inhibitor, a cyclophilin/TNF inhibitor,a TLR-agonist, an HBV vaccine, and agents of distinct or unknownmechanism, and a combination thereof. In a further embodiment, themethods provided herein allow for administering of the at least oneadditional therapeutic agent at a lower dose or frequency as compared tothe administering of the at least one additional therapeutic agent alonethat is required to achieve similar results in prophylactically treatingan HBV infection in an individual in need thereof.

In another embodiment, the methods provided herein reduce the viral loadin the individual to a greater extent or at a faster rate compared tothe administering of a compound selected from the group consisting of anHBV polymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, distinct capsid assembly modulator, antiviralcompounds of distinct or unknown mechanism, and any combination thereof.

In another embodiment, the methods provided herein cause a lowerincidence of viral mutation and/or viral resistance than theadministering of a compound selected from the group consisting of an HBVpolymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, distinct capsid assembly modulator, antiviralcompounds of distinct or unknown mechanism, and combination thereof.

In another embodiment, the methods provided herein further compriseadministering to the individual at least one HBV vaccine, a nucleosideHBV inhibitor, an interferon or any combination thereof.

In an aspect, provided herein is a method of treating an HBV infectionin an individual in need thereof, comprising reducing the HBV viral loadby administering to the individual a therapeutically effective amount ofa compound of Formula I, II, III, or IV, or a pharmaceuticallyacceptable salt thereof, alone or in combination with a reversetranscriptase inhibitor; and further administering to the individual atherapeutically effective amount of HBV vaccine.

In an embodiment, the methods provided herein further comprisemonitoring the HBV viral load of the subject, wherein the method iscarried out for a period of time such that the HBV virus isundetectable.

DETAILED DESCRIPTION

Provided herein are compounds, e.g., the compounds of Formulas I, II,III, or IV, or pharmaceutically acceptable salts thereof, that areuseful in the treatment and prevention of HBV infection in subject. In anon-limiting aspect, these compounds may modulate or disrupt HBVassembly and other HBV core protein functions necessary for HBVreplication or the generation of infectious particles, may inhibit theproduction of infectious virus particles or infection or may interactwith HBV capsid to afford defective viral particles with greatly reducedinfectivity or replication capacity. In other words, the compoundsprovided herein may act as capsid assembly modulators. The compoundsprovided herein have potent antiviral activity, exhibit favorablemetabolic properties, tissue distribution, safety and pharmaceuticalprofiles, and are suitable for use in humans.

The HBV capsid protein plays essential functions during the viral lifecycle. HBV capsid/core proteins form metastable viral particles orprotein shells that protect the viral genome during intercellularpassage, and also play a central role in viral replication processes,including genome encapsidation, genome replication, and virionmorphogenesis and egress. Capsid structures also respond toenvironmental cues to allow un-coating after viral entry. Consistently,the appropriate timing of capsid assembly and dis-assembly, theappropriate capsid stability and the function of core protein have beenfound to be critical for viral infectivity.

The crucial function of HBV capsid proteins imposes stringentevolutionary constraints on the viral capsid protein sequence, leadingto the observed low sequence variability and high conservation.Consistently, mutations in HBV capsid that disrupt its assembly arelethal, and mutations that perturb capsid stability severely attenuateviral replication. The high functional constraints on themulti-functional HBV core/capsid protein is consistent with a highsequence conservation, as many mutations are deleterious to function.Indeed, the core/capsid protein sequences are >90% identical across HBVgenotypes and show only a small number of polymorphic residues.Resistance selection to HBV core/capsid protein binding compounds maytherefore be difficult to select without large impacts on virusreplication fitness.

Reports describing compounds that bind viral capsids and inhibitreplication of HIV, rhinovirus and HBV provide strong pharmacologicalproof of concept for viral capsid proteins as antiviral drug targets.

In one aspect, the compounds provided herein are useful in HBV treatmentby disrupting, accelerating, reducing, delaying and/or inhibiting normalviral capsid assembly and/or disassembly of immature or matureparticles, thereby inducing aberrant capsid morphology and leading toantiviral effects such as disruption of virion assembly and/ordisassembly, virion maturation, virus egress and/or infection of targetcells. In one embodiment, a disruptor of capsid assembly interacts withmature or immature viral capsid to perturb the stability of the capsid,thus affecting assembly and/or disassembly. In another embodiment, adisruptor of capsid assembly perturbs protein folding and/or saltbridges required for stability, function and/or normal morphology of theviral capsid, thereby disrupting and/or accelerating capsid assemblyand/or disassembly. In yet another embodiment, the compounds of theinvention bind capsid and alter metabolism of cellular polyproteins andprecursors, leading to abnormal accumulation of protein monomers and/oroligomers and/or abnormal particles, which causes cellular toxicity anddeath of infected cells. In another embodiment, the compounds providedherein cause failure of the formation of capsids of optimal stability,affecting efficient uncoating and/or disassembly of viruses (e.g.,during infectivity).

In one embodiment, the compounds provided herein disrupt and/oraccelerate capsid assembly and/or disassembly when the capsid protein isimmature. In another embodiment, the compounds provided herein disruptand/or accelerate capsid assembly and/or disassembly when the capsidprotein is mature. In yet another embodiment, the compounds providedherein disrupt and/or accelerate capsid assembly and/or disassemblyduring viral infectivity. In yet another embodiment, the disruptionand/or acceleration of capsid assembly and/or disassembly attenuates HBVviral infectivity and/or reduces viral load. In yet another embodiment,disruption, acceleration, inhibition, delay and/or reduction of capsidassembly and/or disassembly eradicates the virus from the host organism.In yet another embodiment, eradication of the HBV from a hostadvantageously obviates the need for chronic long-term therapy and/orreduces the duration of long-term therapy.

In one embodiment, the compounds described herein are suitable formonotherapy and are effective against natural or native HBV strains andagainst HBV strains resistant to currently known drugs. In anotherembodiment, the compounds described herein are suitable for use incombination therapy.

In another embodiment, the compounds proided herein can be used inmethods of modulating (e.g., inhibiting or disrupting) the activity,stability, function, and viral replication properties of HBV cccDNA. Inyet another embodiment, the compounds of the invention can be used inmethods of diminishing or preventing the formation of HBV cccDNA.

In another embodiment, the the compounds provided herein can be used inmethods of modulating (e.g., inhibiting or disrupting) the activity ofHBV cccDNA. In yet another embodiment, the compounds of the inventioncan be used in methods of diminishing the formation of HBV cccDNA.

In another embodiment, the the compounds provided herein can be used inmethods of modulating, inhibiting, or disrupting the generation orrelease of HBV RNA particles from within the infected cell. In a furtherembodiment, the total burden (or concentration) of HBV RNA particles ismodulated. In a preferred embodiment, the total burden of HBV RNA isdiminished.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Generally,the nomenclature used herein and the laboratory procedures in cellculture, molecular genetics, organic chemistry, and peptide chemistryare those well-known and commonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more thanone (i.e. to at least one) of the grammatical object of the article. Byway of example, “an element” means one element or more than one element.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

As used herein, the term “about” will be understood by persons ofordinary skill in the art and will vary to some extent on the context inwhich it is used. As used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, the term “about”is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%,and ±0.1% from the specified value, as such variations are appropriateto perform the disclosed methods.

As used herein, the term “capsid assembly modulator” refers to acompound that disrupts or accelerates or inhibits or hinders or delaysor reduces or modifies normal capsid assembly (e.g., during maturation)or normal capsid disassembly (e.g., during infectivity) or perturbscapsid stability, thereby inducing aberrant capsid morphology andfunction. In one embodiment, a capsid assembly modulator acceleratescapsid assembly or disassembly, thereby inducing aberrant capsidmorphology. In another embodiment, a capsid assembly modulator interacts(e.g. binds at an active site, binds at an allosteric site, modifiesand/or hinders folding and the like) with the major capsid assemblyprotein (CA), thereby disrupting capsid assembly or disassembly. In yetanother embodiment, a capsid assembly modulator causes a perturbation instructure or function of CA (e.g., ability of CA to assemble,disassemble, bind to a substrate, fold into a suitable conformation, orthe like), which attenuates viral infectivity and/or is lethal to thevirus.

As used herein, the term “treatment” or “treating,” is defined as theapplication or administration of a therapeutic agent, i.e., a compoundof the invention (alone or in combination with another pharmaceuticalagent), to a patient, or application or administration of a therapeuticagent to an isolated tissue or cell line from a patient (e.g., fordiagnosis or ex vivo applications), who has an HBV infection, a symptomof HBV infection or the potential to develop an HBV infection, with thepurpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate,improve or affect the HBV infection, the symptoms of HBV infection orthe potential to develop an HBV infection. Such treatments may bespecifically tailored or modified, based on knowledge obtained from thefield of pharmacogenomics.

As used herein, the term “prevent” or “prevention” means no disorder ordisease development if none had occurred, or no further disorder ordisease development if there had already been development of thedisorder or disease. Also considered is the ability of one to preventsome or all of the symptoms associated with the disorder or disease.

As used herein, the term “patient,” “individual” or “subject” refers toa human or a non-human mammal. Non-human mammals include, for example,livestock and pets, such as ovine, bovine, porcine, canine, feline andmurine mammals. Preferably, the patient, subject or individual is human.As used herein, the terms “effective amount,” “pharmaceuticallyeffective amount” and “therapeutically effective amount” refer to anontoxic but sufficient amount of an agent to provide the desiredbiological result. That result may be reduction and/or alleviation ofthe signs, symptoms, or causes of a disease, or any other desiredalteration of a biological system. An appropriate therapeutic amount inany individual case may be determined by one of ordinary skill in theart using routine experimentation.

As used herein, the term “pharmaceutically acceptable” refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound, and is relativelynon-toxic, i.e., the material may be administered to an individualwithout causing undesirable biological effects or interacting in adeleterious manner with any of the components of the composition inwhich it is contained.

As used herein, the term “pharmaceutically acceptable salt” refers toderivatives of the disclosed compounds wherein the parent compound ismodified by converting an existing acid or base moiety to its salt form.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts of thepresent invention include the conventional non-toxic salts of the parentcompound formed, for example, from non-toxic inorganic or organic acids.The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

As used herein, the term “composition” or “pharmaceutical composition”refers to a mixture of at least one compound useful within the inventionwith a pharmaceutically acceptable carrier. The pharmaceuticalcomposition facilitates administration of the compound to a patient orsubject. Multiple techniques of administering a compound exist in theart including, but not limited to, intravenous, oral, aerosol,parenteral, ophthalmic, pulmonary and topical administration.

As used herein, the term “pharmaceutically acceptable carrier” means apharmaceutically acceptable material, composition or carrier, such as aliquid or solid filler, stabilizer, dispersing agent, suspending agent,diluent, excipient, thickening agent, solvent or encapsulating material,involved in carrying or transporting a compound useful within theinvention within or to the patient such that it may perform its intendedfunction. Typically, such constructs are carried or transported from oneorgan, or portion of the body, to another organ, or portion of the body.Each carrier must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation, including the compound usefulwithin the invention, and not injurious to the patient. Some examples ofmaterials that may serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; surface active agents; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffersolutions; and other non-toxic compatible substances employed inpharmaceutical formulations.

As used herein, “pharmaceutically acceptable carrier” also includes anyand all coatings, antibacterial and antifungal agents, and absorptiondelaying agents, and the like that are compatible with the activity ofthe compound useful within the invention, and are physiologicallyacceptable to the patient. Supplementary active compounds may also beincorporated into the compositions. The “pharmaceutically acceptablecarrier” may further include a pharmaceutically acceptable salt of thecompound useful within the invention. Other additional ingredients thatmay be included in the pharmaceutical compositions used in the practiceof the invention are known in the art and described, for example inRemington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co.,1985, Easton, Pa.), which is incorporated herein by reference.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent means, unless otherwise stated, a straight or branched chainhydrocarbon having the number of carbon atoms designated (i.e.,C₁-C₆-alkyl means one to six carbon atoms) and includes straight,branched chain Examples include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples ofC₁-C₆-alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, andn-hexyl.

As used herein, the term “alkenyl,” denotes a monovalent group derivedfrom a hydrocarbon moiety containing at least two carbon atoms and atleast one carbon-carbon double bond. The double bond may or may not bethe point of attachment to another group. Alkenyl groups (e.g.,C₂-C₈-alkenyl) include, but are not limited to, for example, ethenyl,propenyl, prop-1-en-2-yl, butenyl, 1-methyl-2-buten-1-yl, heptenyl,octenyl and the like.

As used herein, the term “halo” or “halogen” alone or as part of anothersubstituent means, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom, preferably, fluorine, chlorine, or bromine,more preferably, fluorine or chlorine.

As used herein, the term “haloalkyl” refers to alkl radicals wherein anyone or more of the alkyl carbon atoms is substituted with halo asdefined above. Haloalkyl embraces monohaloalkyl, dihaloalkyl, andpolyhaloalkyl radicals. The term “haloalkyl” includes, but is notlimited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, and pentafluoroethyl.

As used herein, the term “cycloalkyl” refers to a mono cyclic orpolycyclic nonaromatic radical, wherein each of the atoms forming thering (i.e., skeletal atoms) is a carbon atom. In one embodiment, thecycloalkyl group is saturated or partially unsaturated. In anotherembodiment, the cycloalkyl group is fused with an aromatic ring.Cycloalkyl groups include groups having 3 to 10 ring atoms(C₃-C₁₀-cycloalkyl), groups having 3 to 8 ring atoms (C₃-C₈-cycloalkyl),groups having 3 to 7 ring atoms (C₃-C₇-cycloalkyl), and groups having 3to 6 ring atoms (C₃-C₆-cycloalkyl). Illustrative examples of cycloalkylgroups include, but are not limited to, the following moieties:

Monocyclic cycloalkyls include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.Dicyclic cycloalkyls include, but are not limited to,tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycycliccycloalkyls include adamantine and norbornane. The term cycloalkylincludes “unsaturated nonaromatic carbocyclyl” or “nonaromaticunsaturated carbocyclyl” groups, both of which refer to a nonaromaticcarbocycle as defined herein, which contains at least one carbon carbondouble bond or one carbon carbon triple bond.

As used herein, the term “heterocycloalkyl” or “heterocyclyl” refers toa heteroalicyclic group containing one to four ring heteroatoms eachselected from O, S and N. In one embodiment, each heterocyclyl group hasfrom 3 to 10 atoms in its ring system, with the proviso that the ring ofsaid group does not contain two adjacent O or S atoms. Heterocyclylsubstituents may be alternatively defined by the number of carbon atoms,e.g., C₂-C₈-heterocyclyl indicates the number of carbon atoms containedin the heterocyclic group without including the number of heteroatoms.For example, a C₂-C₈-heterocyclyl will include an additional one to fourheteroatoms. In another embodiment, the heterocycloalkyl group is fusedwith an aromatic ring. In one embodiment, the nitrogen and sulfurheteroatoms may be optionally oxidized, and the nitrogen atom may beoptionally quaternized. The heterocyclic system may be attached, unlessotherwise stated, at any heteroatom or carbon atom that affords a stablestructure.

An example of a 3-membered heterocyclyl group includes, and is notlimited to, aziridine. Examples of 4-membered heterocyclyl groupsinclude, and are not limited to, azetidine and a beta lactam. Examplesof 5-membered heterocyclyl groups include, and are not limited to,pyrrolidine, oxazolidine and thiazolidinedione. Examples of 6-memberedheterocycloalkyl groups include, and are not limited to, piperidine,morpholine and piperazine.

Other non-limiting examples of heterocyclyl groups are:

Examples of heterocycles include monocyclic groups such as aziridine,oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline,pyrazolidine, imidazoline, dioxolane, sulfolane, 2,3-dihydrofuran,2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine,1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine,thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane,1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin, and hexamethyleneoxide.

As used herein, the term “aromatic” refers to a carbocycle orheterocycle with one or more polyunsaturated rings and having aromaticcharacter, i.e., having (4n+2) delocalized 7E (pi) electrons, where n isan integer.

As used herein, the term “aryl,” employed alone or in combination withother terms, means, unless otherwise stated, a carbocyclic aromaticsystem containing one or more rings (typically one, two, or threerings), wherein such rings may be attached together in a pendent manner,such as a biphenyl, or may be fused, such as naphthalene. Examples ofaryl groups include phenyl, anthracyl, and naphthyl. Preferred examplesare phenyl (e.g., C₆-aryl) and biphenyl (e.g., C₁₂-aryl). In someembodiments, aryl groups have from six to sixteen carbon atoms. In someembodiments, aryl groups have from six to twelve carbon atoms (e.g.,C₆-C₁₂-aryl). In some embodiments, aryl groups have six carbon atoms(e.g., C₆-aryl).

As used herein, the term “heteroaryl” or “heteroaromatic” refers to aheterocycle having aromatic character. Heteroaryl substituents may bedefined by the number of carbon atoms, e.g., C₁-C₉-heteroaryl indicatesthe number of carbon atoms contained in the heteroaryl group withoutincluding the number of heteroatoms. For example, a C₁-C₉-heteroarylwill include an additional one to four heteroatoms. A polycyclicheteroaryl may include one or more rings that are partially saturated.Non-limiting examples of heteroaryls include:

Additional non-limiting examples of heteroaryl groups include pyridyl,pyrazinyl, pyrimidinyl (including, e.g., 2- and 4-pyrimidinyl),pyridazinyl, thienyl, furyl, pyrrolyl (including, e.g., 2-pyrrolyl),imidazolyl, thiazolyl, oxazolyl, pyrazolyl (including, e.g., 3- and5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

Non-limiting examples of polycyclic heterocycles and heteroaryls includeindolyl (including, e.g., 3-, 4-, 5-, 6- and 7-indolyl), indolinyl,quinolyl, tetrahydroquinolyl, isoquinolyl (including, e.g., 1- and5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl(including, e.g., 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl,1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin,1,5-naphthyridinyl, benzofuryl (including, e.g., 3-, 4-, 5-, 6- and7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl(including, e.g., 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl,benzothiazolyl (including, e.g., 2-benzothiazolyl and 5-benzothiazolyl),purinyl, benzimidazolyl (including, e.g., 2-benzimidazolyl),benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl,pyrrolizidinyl, and quinolizidinyl.

As used herein, the term “substituted” means that an atom or group ofatoms has replaced hydrogen as the substituent attached to anothergroup.

Compounds of the Invention

Provided herein are compounds useful for the treatment of HBV infectionin a subject in need thereof, having the structure:

or pharmaceutically acceptable salts thereof.

In one aspect, provided herein is a compound of Formula Ia

or a pharmaceutically acceptable salt thereof,

wherein

W¹ and W are each independently selected from N, NR^(a), and CR^(a),wherein one of W¹ and W is NR^(a);

X is N or CR^(b);

Y is selected from a bond, —C(O)—, and —SO₂—;

Z is selected from —(CR⁵R⁶)_(m), —(CR⁵R⁶)_(m)O—, —(CR⁵R⁶)_(m)CR⁵═CR⁵—,—(CR⁵R⁶)_(m)—C₃-C₆-cycloalkylene-, and —(CR⁵R⁶)_(m)—NR⁷—;

R¹ is selected from C₆-C₁₂-aryl, C₁-C₉-heteroaryl, C₃-C₈-cycloalkyl,C₂-C₈-heterocyclyl, —OR^(c), C₁-C₆-alkyl, C(O)OR^(c), C(O)R^(c),C(O)NR^(d)R^(e), NR^(d)C(O)R^(c), —OC(O)R^(c), halo, and C₂-C₈-alkenyl,wherein alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkenylare optionally substituted with 1, 2, 3, or 4 groups each independentlyselected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl,and C₁-C₆-alkyl-OH;

R² is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R³ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁴ is selected from C₁-C₆-alkyl, (CR⁸R⁹)_(p)—C₃-C₈-cycloalkyl,(CR⁸R⁹)_(p)—C₂-C₈-heterocyclyl, (CR⁸R⁹)_(p)—C₆-C₁₂-aryl, and(CR⁸R⁹)_(p)—C₁-C₉-heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4groups, each independently selected from —OH, halo, CN, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C(O)N(R^(f))₂, C(O)OR^(f),—OCH₂C(O)OR^(f), —SO₂R^(f), C₁-C₆-alkyl-OH, and C₃-C₈-cycloalkyl;

R⁵ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

alternatively, R⁴ and R⁵ are optionally joined to form a ring;

R⁶ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁷ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁸ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁹ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(a) is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(b) is selected from H and C₁-C₆-alkyl;

R^(c) is selected from H, C₁-C₆-alkyl, C₁-C₆-alkyl-OH, C₃-C₅-cycloalkyl,C₂-C₅-heterocyclyl, C₆-C₁₂-aryl, and C₁-C₉-heteroaryl;

R^(d) is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(e) is selected from H, C₁-C₆-alkyl, C₁-C₆-alkyl-OH, C₃-C₅-cycloalkyl,C₂-C₅-heterocyclyl, C₆-C₁₂-aryl, C₁-C₉-heteroaryl, and —O—C₁-C₆-alkyl;

alternatively, R^(d) and R^(e) are optionally joined to form aheterocyclic ring;

R^(f) is, at each occurrence, independently selected from H andC₁-C₆-alkyl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

p is 0, 1, 2, 3, or 4.

In another aspect, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof,

wherein

W¹ and W are each independently selected from N, NR^(a), and CR^(a),wherein one of W¹ and W is NR^(a).

X is N or CR^(b);

Y is selected from a bond, —C(O)—, and —SO₂—;

Z is selected from —(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(m)O—, —(CR⁵R⁶)_(m)CR⁵═CR⁵—,—(CR⁵R⁶)_(m)—C₃-C₆-cycloalkylene-, and —(CR⁵R⁶)_(m)—NR⁷—;

R¹ is selected from C₆-C₁₂-aryl and C₁-C₉-heteroaryl, wherein aryl andheteroaryl are optionally substituted with 1, 2, 3, or 4 groups eachindependently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, CN, and C(O)H;

R² is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R³ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁴ is selected from C₁-C₆-alkyl, (CR⁸R⁹)_(p)—C₃-C₈-cycloalkyl,(CR⁸R⁹)_(p)—C₂-C₈-heterocyclyl, (CR⁸R⁹)_(p)—C₆-C₁₂-aryl, and(CR⁸R⁹)_(p)—C₁-C₉-heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4groups, each independently selected from —OH, halo, CN, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C(O)N(R^(f))₂, C(O)OR^(f),—OCH₂C(O)OR^(f), —SO₂R^(f), C₁-C₆-alkyl-OH, C₃-C₈-cycloalkyl, andC₆-aryl;

R⁵ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

alternatively, R⁴ and R⁵ are optionally joined to form a heterocyclicring;

R⁶ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁷ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁸ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁹ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(a) is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(b) is selected from H and C₁-C₆-alkyl;

R^(f) is, at each occurrence, independently selected from H andC₁-C₆-alkyl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

p is 0, 1, 2, 3, or 4.

In an embodiment of the compound of Formula I

or a pharmaceutically acceptable salt thereof,

W¹ and W are each independently selected from N, NR^(a), and CR^(a),wherein one of W¹ and W is NR^(a);

X is N or CR^(b);

Y is selected from a bond, —C(O)—, and —SO₂—;

Z is selected from —(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(m)O—, —(CR⁵R⁶)_(m)CR⁵═CR⁵—,—(CR⁵R⁶)_(m)—C₃-C₆-cycloalkylene-, and —(CR⁵R⁶)_(m)—NR⁷—;

R¹ is selected from C₆-C₁₂-aryl and C₁-C₉-heteroaryl, wherein aryl andheteroaryl are optionally substituted with 1 or 2 groups eachindependently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, CN, and C(O)HH;

R² is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R³ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁴ is selected from C₁-C₆-alkyl, (CR⁸R⁹)_(p)—C₃-C₈-cycloalkyl,(CR⁸R⁹)_(p)—C₂-C₈-heterocyclyl, (CR⁸R⁹)_(p)—C₆-C₁₂-aryl, and(CR⁸R⁹)_(p)—C₁-C₉-heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4groups, each independently selected from —OH, halo, CN, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C(O)N(R^(f))₂, C(O)OR^(f),—OCH₂C(O)OR^(f), —SO₂R^(f), and C₁-C₆-alkyl-OH;

R⁵ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

alternatively, R⁴ and R⁵ are optionally joined to form a ring;

R⁶ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁷ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁸ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁹ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(a) is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(b) is selected from H and C₁-C₆-alkyl;

R^(f) is, at each occurrence, independently selected from H andC₁-C₆-alkyl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

p is 0, 1, 2, 3, or 4.

In another embodiment of the compound of Formula I, W¹ is NR^(a) and Wis N or CR^(a). In a further embodiment, W¹ is NH.

In another embodiment of the compound of Formula I, W¹ is N or CR^(a)and W is NR^(a).

In another embodiment of the compound of Formula I, X is N.

In an embodiment of the compound of Formula I, Y is —C(O)— or —SO₂—.

In a further embodiment of the compound of Formula I, Z is—(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(m)O—, or —(CR⁵R⁶)_(m)—NR⁷—.

In an embodiment of the compound of Formula I,

m is 0 or 1;

R⁵ is H, —OH, or C₁-C₆-alkyl;

R⁶ is H or C₁-C₆-alkyl; and

R⁷ is H or C₁-C₆-alkyl.

In an embodiment of the compound of Formula I, R¹ is C₆-aryl orC₁-C₉-heteroaryl wherein aryl and heteroaryl are optionally substitutedwith 1 or 2 groups independently selected from —OH, halo, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, CN, and C(O)H.

In another embodiment of the compound of Formula I, R¹ is C₆-aryl,pyrimidinyl, pyridinyl, pyrazolyl, thiophenyl, thiazolyl, isothiazolyl,oxazolyl, pyridazinyl, pyrazinyl, or pyrrolyl, any of which areoptionally substituted by 1 or 2 groups independently selected from —OH,halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, CN,and C(O)H.

In an embodiment of the compound of Formula I, each R² is independentlyselected from H, C₁-C₆-alkyl, or C₁-C₆-alkyl-OH. In a further embodimentof the compound of Formula I, each R² is independently selected fromC₁-C₆-alkyl or H. In yet a further embodiment of the compound of FormulaI, R² is H.

In an embodiment of the compound of Formula I, R³ is H or C₁-C₆-alkyl.

In an embodiment of the compound of Formula I, R⁴ is(CR⁸R⁹)_(p)—C₃-C₈-cycloalkyl, (CR⁸R⁹)_(p)—C₂-C₈-heterocyclyl,(CR⁸R⁹)_(p)—C₆-C₁₂-aryl, or (CR⁸R⁹)_(p)—C₁-C₉-heteroaryl, whereincycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with 1, 2, 3, or 4 groups each independently selected from—OH, halo, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl,C(O)N(R^(f))₂, C(O)OR^(f), —OCH₂C(O)OR^(f), —SO₂R^(f), andC₁-C₆-alkyl-OH.

In another embodiment of the compound of Formula I, R⁴ is(CR⁸R⁹)_(p)—C₆-C₁₂-aryl, or (CR⁸R⁹)_(p)—C₁-C₉-heteroaryl, wherein aryl,and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups,each independently selected from —OH, halo, CN, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C(O)N(R^(f))₂, C(O)OR^(f),—OCH₂C(O)OR^(f), —SO₂R^(f), and C₁-C₆-alkyl-OH.

In another embodiment of the compound of Formula I,

p is 0 or 1;

R⁸ is H, —OH, or C₁-C₆-alkyl; and

R⁹ is H or C₁-C₆-alkyl.

In an embodiment of the compound of Formula I, n is 1.

In another embodiment of the compound of Formula I,

X is N;

Y is —C(O)—;

Z is NR⁷; and

R⁷ is H or C₁₋₄-alkyl.

In a further embodiment of the compound of Formula I,

X is N;

Y is —C(O)—;

Z is NR⁷;

R⁷ is H or C₁₋₄-alkyl; and

n is 1.

Also provided herein is a compound of Formula I, having the structure ofFormula II (also referred to as “a compound of Formula II”):

or a pharmaceutically acceptable salt thereof.

In an embodiment of the compound of Formula II, Y is —C(O)— or —SO₂—.

In an embodiment of the compound of Formula II, Z is —(CR⁵R⁶)_(m),—(CR⁵R⁶)_(m)O— or —(CR⁵R⁶)_(m)—NR⁷—.

In an embodiment of the compound of Formula II,

m is 0 or 1;

R⁵ is H, —OH, or C₁-C₆-alkyl;

R⁶ is H or C₁-C₆-alkyl; and

R⁷ is H or C₁-C₆-alkyl.

In an embodiment of the compound of Formula II, R¹ is C₆-C₁₂-aryl orC₁-C₉-heteroaryl, wherein aryl and heteroaryl are optionally substitutedwith 1 or 2 groups each independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, CN, andC(O)H.

In another embodiment of the compound of Formula II, R¹ is C₆-aryl,pyrimidinyl, pyridinyl, pyrazolyl, thiophenyl, thiazolyl, isothiazolyl,oxazolyl, pyridazinyl, pyrazinyl, or pyrrolyl, any of which areoptionally substituted by 1 or 2 groups independently selected from —OH,halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, CN,and C(O)H.

In an embodiment of the compound of Formula II, each R² is independentlyselected from H, C₁-C₆-alkyl, or C₁-C₆-alkyl-OH. In a further embodimentof the compound of Formula II, each R² is independently selected fromC₁-C₆-alkyl or H. In yet a further embodiment of the compound of FormulaII, R² is H.

In an embodiment of the compound of Formula II, R³ is H or C₁-C₆-alkyl.In a further embodiment, R³ is H.

In an embodiment of the compound of Formula II, n is 1.

In an embodiment of the compound of Formula II, R⁴ is(CR⁸R⁹)_(p)—C₃-C₈-cycloalkyl, (CR⁸R⁹)_(p)—C₂—C s-heterocyclyl,(CR⁸R⁹)_(p)—C₆-C₁₂-aryl, or (CR⁸R⁹)_(p)—C₁-C₉-heteroaryl, whereincycloalkyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with 1, 2, 3, or 4 groups, each independently selected from—OH, halo, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl,C(O)N(R^(f))₂, C(O)OR^(f), —OCH₂C(O)OR^(f), —SO₂R^(f), andC₁-C₆-alkyl-OH.

In an embodiment of the compound of Formula II, R⁴ is(CR⁸R⁹)_(p)—C₆-C₁₂-aryl, or (CR⁸R⁹)_(p)—C₁-C₉-heteroaryl, and whereinaryl and heteroaryl are optionally substituted with 1, 2, 3, or 4groups, each independently selected from —OH, halo, CN, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C(O)N(R^(f))₂, C(O)OR^(f),—OCH₂C(O)OR^(f), —SO₂R^(f), and C₁-C₆-alkyl-OH.

In an embodiment of the compound of Formula II,

Y is —C(O)—;

Z is —(CR⁵R⁶)_(m), —(CR⁵R⁶)_(m)O— or —(CRR⁶)_(m)—NR⁷—;

R¹ is C₆-aryl, pyrimidinyl, pyridinyl, pyrazolyl, thiophenyl, thiazolyl,isothiazolyl, oxazolyl, pyridazinyl, pyrazinyl, or pyrrolyl, any ofwhich are optionally substituted by 1 or 2 groups independently selectedfrom —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl,C₁-C₆-alkyl-OH, CN, and C(O)Heach R² is independently selected from H,C₁-C₆-alkyl, or C₁-C₆-alkyl-OH and R³ is H;

R⁴ is (CR⁸R⁹)_(p)—C₆-C₁₂-aryl, or (CR⁸R⁹)_(p)—C₁-C₉-heteroaryl, andwherein aryl and heteroaryl are optionally substituted with 1, 2, 3, or4 groups, each independently selected from —OH, halo, CN, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C(O)N(R^(f))₂, C(O)OR^(f),—OCH₂C(O)OR^(f), —SO₂R^(f), and C₁-C₆-alkyl-OH;

R⁵ is H, —OH, or C₁-C₆-alkyl;

R⁶ is H or C₁-C₆-alkyl;

R⁷ is H or C₁-C₆-alkyl;

R⁸ is, at each occurrence, independently selected from H, —OH, halo, andC₁-C₆-alkyl;

R⁹ is, at each occurrence, independently selected from H, —OH, halo, andC₁-C₆-alkyl;

R^(f) is, at each occurrence, independently selected from H andC₁-C₆-alkyl;

m is 1 or 2;

n is 1; and

p is 0, 1, or 2.

In an embodiment of this embodiment, R¹ is C₆-aryl, optionallysubstituted by —OH or halo.

In an embodiment of this embodiment, R¹ is C₆-aryl, optionallysubstituted with halo.

In an embodiment of this embodiment, R⁴ is (CR⁸R⁹)_(p)—C₆-C₁₂-aryl, or(CR⁸R⁹)_(p)—C₁-C₉-heteroaryl, and wherein aryl and heteroaryl areoptionally substituted with 1, 2, or 3 groups, each independentlyselected from —OH, halo, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH.

In an embodiment of the compound of Formula II,

p is 0 or 1;

R⁸ is independently selected from H, —OH, and C₁-C₆-alkyl; and

R⁹ is independently selected from H and C₁-C₆-alkyl.

In an embodiment of the compound of Formula II, n is 1.

In an embodiment of the compound of Formula II,

Y is —C(O)—;

Z is NR⁷; and

R⁷ is H or C₁₋₄-alkyl.

In an embodiment of the compound of Formula II,

Y is —C(O)—;

Z is NR⁷;

R⁷ is H or C₁₋₄-alkyl; and

n is 1.

Also provided herein is a compound of Formula I, having the structure ofFormula III (also referred to as “a compound of Formula III”):

or a pharmaceutically acceptable salt thereof, wherein

Y is —C(O)— or —SO₂—;

R¹ is C₆-C₁₂-aryl or C₁-C₉-heteroaryl, wherein aryl and heteroaryl areoptionally substituted with 1 or 2 groups each independently selectedfrom —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl,C₁-C₆-alkyl-OH, CN, and C(O)H;

R² is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R³ is selected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁴ is selected from (CR⁸R⁹)_(p)—C₁-C₉-heteroaryl,(CR⁸R⁹)_(p)—C₆-C₁₂-aryl, and C₃-C₅-cycloalkyl wherein heteroaryl, aryl,and cycloalkyl are optionally substituted with 1, 2, or 3 groups, eachindependently selected from —OH, halo, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, and C₃-C₅-cycloalkyl.

R⁷ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁸ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁹ is, at each occurrence, independently selected from H andC₁-C₆-alkyl; and

p is 0, 1, 2, 3, or 4.

In an embodiment of the Compound of Formula III

Y is —C(O)— or —SO₂—;

R¹ is C₆-aryl, pyrimidinyl, pyridinyl, pyrazolyl, thiophenyl, thiazolyl,isothiazolyl, oxazolyl, pyridazinyl, pyrazinyl, or pyrrolyl, any ofwhich are optionally substituted by 1 or 2 groups independently selectedfrom —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl,C₁-C₆-alkyl-OH, CN, and C(O)H;

R² is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R³ is selected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁴ is selected from (CR⁸R⁹)_(p)—C₁-C₉-heteroaryl and(CR⁸R⁹)_(p)—C₆-C₁₂-aryl, wherein heteroaryl and aryl are optionallysubstituted with 1, 2, or 3 groups, each independently selected from—OH, halo, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, andC₁-C₆-alkyl-OH.

R⁷ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁸ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁹ is, at each occurrence, independently selected from H andC₁-C₆-alkyl; and

p is 0, 1, 2, 3, or 4.

In an embodiment of the compound of Formula III, Y is —C(O)—.

In an embodiment of the compound of Formula III, R¹ is C₆-aryl, orC₁-C₉-heteroaryl, wherein aryl or heteroaryl are optionally substitutedby —OH, halo, C₁-C₆-alkyl, or —O—C₁-C₆-alkyl.

In an embodiment of the compound of Formula III, R¹ is C₆-aryl, C₆-aryl,pyrimidinyl, pyridinyl, pyrazolyl, thiophenyl, thiazolyl, isothiazolyl,oxazolyl, or pyridazinyl, any of which are optionally substituted by 1or 2 groups independently selected from —OH, halo, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, CN, and C(O)H.

In another embodiment of the compound of Formula III, R¹ is C₆-aryl.

In another embodiment of the compound of Formula III, each R² isindependently selected from H, C₁-C₆-alkyl, or C₁-C₆-alkyl-OH. In afurther embodiment of the compound of Formula III, each R² isidependantly selected from C₁-C₆-alkyl or H. In yet a further embodimentof the compound of Formula III, R² is H.

In an embodiment of the compound of Formula III, R³ is H or C₁-C₆-alkyl.In a further embodiment of the compound of Formula III, R³ is H.

In an embodiment of the compound of Formula III, R⁷ is H or C₁-C₄-alkyl.In a further embodiment, R⁷ is H or —CH₃. In yet another embodiment, R⁷is H.

In an embodiment of the compound of Formula III, R⁴ is(CR⁸R⁹)_(p)—C₁-C₅-heteroaryl or (CR⁸R⁹)_(p)—C₆-aryl, orC₃-C₅-cycloalkyl, wherein heteroaryl, aryl and cycloalkyl are optionallysubstituted with 1, 2, or 3 groups, each independently selected from—OH, halo, CN, and C₁-C₆-alkyl;

R⁸ is H or C₁-C₆-alkyl;

R⁹ is H or C₁-C₆-alkyl; and

p is 0 or 1.

In an embodiment of the compound of Formula III, R⁴ is(CR⁸R⁹)_(p)—C₁-C₅-heteroaryl or (CR⁸R⁹)_(p)—C₆-aryl, wherein heteroaryland aryl are optionally substituted with 1, 2, or 3 groups, eachindependently selected from —OH, halo, CN, and C₁-C₆-alkyl;

R⁸ is H or C₁-C₆-alkyl;

R⁹ is H or C₁-C₆-alkyl; and

p is 0 or 1.

In a particular embodiment of the compound of Formula III, R⁴ is

In another particular embodiment of the compound of Formula III, R⁴ is

In another particular embodiment of the compound of Formula III, R⁴ is

Also provided herein is a compound of Formula I, having the structure ofFormula IV (also referred to as “a compound of Formula IV”):

or a pharmaceutically acceptable salt thereof wherein,

Y is —C(O)— or —SO₂—; and

m is 0, 1, or 2.

In an embodiment of the compound of Formula IV, Y is —C(O)—.

In an embodiment of the compound of Formula IV, R¹ is C₆-C₁₂-aryl orC₁-C₉-heteroaryl, wherein aryl and heteroaryl are optionally substitutedwith 1 or 2 groups each independently selected from —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, and CN. Inan embodiment of the compound of Formula IV, R¹ is C₆-aryl optionallysubstituted by —OH or halo.

In an embodiment of the compound of Formula IV, R² is H.

In an embodiment of the compound of Formula IV, R³ is H.

In another embodiment of the compound of Formula IV, m is 1, R⁵ is H orC₁-C₆-alkyl, R⁶ is H or C₁-C₆-alkyl, and wherein R⁵ and R⁴ areoptionally joined to form a ring. In another embodiment of the compoundof Formula IV, m is 1; R⁵ is C₁-C₆-alkyl; R⁶ is H or C₁-C₆-alkyl; and R⁵and R⁴ are optionally joined to form a ring. For example, in anembodiment,

is

In another embodiment of the compound of Formula IV, R⁴ is C₁-C₆-alkylor (CR⁸R⁹)_(p)C₆-C₁₂-aryl, wherein alkyl and aryl are optionallysubstituted with 1, 2, or 3, groups, each independently selected from—OH, halo, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl,C(O)N(R^(f))₂, C(O)OR^(f), —OCH₂C(O)OR^(f), —SO₂R^(f), andC₁-C₆-alkyl-OH.

In further embodiments of the compound of Formula IV, R⁴ is

Certain embodiments of Formulas I-IV, including pharmaceuticallyacceptable salts thereof, are shown below in Table 1. All compounds ofFormula I, II, III, and IV as well as pharmaceutically acceptable saltsthereof, and the compounds of Table 1, as well as pharmaceuticallyacceptable salts thereof, are considered to be “compounds of theinvention.”

TABLE 1

001

002

075

010

059

011

060

012

061

013

062

056

063

024

016

187

004

188

005

008

025

026

027

028

029

030

057

017

018

019

020

021

022

023

014

015

064

065

066

067

068

069

070

073

074

085

081

104

095

098

088

093

089

087

119

113

117

114

130

112

078

079

077

082

086

080

092

094

091

097

100

096

103

105

101

107

108

106

111

109

009

240

003

243

244

242

143

144

142

147

148

145

150

151

149

153

154

152

156

157

155

159

160

158

162

163

161

165

169

164

171

172

170

174

175

173

177

178

176

182

183

180

184

190

191

192

201

204

205

214

226

276

277

278

279

280

281

291

325

326

327

286

472

473

495

562

496

497

555

287

436

556

559

560

317

318

576

751

569

726

730

645

568

570

729

741

707

708

712

715

769

766

747

756

754

753

819

820 (851)

821 (852)

822

823 (853)

824 (854)

825

826 (855)

857 (856)

830

831

832

917

918

919

920

921

922

923

924

289

290

716

In yet another embodiment of Formula I provided herein, the compound ofFormula III, or a pharmaceutically acceptable salt thereof, is selectedfrom compounds shown in Table 2 and pharmaceutically acceptable saltsthereof.

TABLE 2

017

018

019

020

022

023

085

081

104

095

098

088

093

089

087

119

113

117

114

130

112

078

079

077

082

086

080

092

094

091

097

100

096

103

105

101

107

108

106

111

109

716

190

191

192

201

204

205

214

226

276

277

278

279

280

281

291

325

326

327

286

472

473

495

562

496

497

555

287

436

556

559

560

317

318

576

751

569

726

730

645

568

570

729

741

707

708

712

715

769

766

747

756

754

753

819

820 (851)

821 (852)

822

823 (853)

824 (854)

825

826 (855)

857 (856)

830

831

832

917

918

919

920

921

922

923

924

289

290

and pharmaceutically acceptable salts thereof.

Also provided herein are the following compounds:

The compounds of the invention may possess one or more stereocenters,and each stereocenter may exist independently in either the R or Sconfiguration. In one embodiment, compounds described herein are presentin optically active or racemic forms. It is to be understood that thecompounds described herein encompass racemic, optically-active,regioisomeric and stereoisomeric forms, or combinations thereof thatpossess the therapeutically useful properties described herein.

Preparation of optically active forms is achieved in any suitablemanner, including by way of non-limiting example, by resolution of theracemic form with recrystallization techniques, synthesis fromoptically-active starting materials, chiral synthesis, orchromatographic separation using a chiral stationary phase. In oneembodiment, a mixture of one or more isomer is utilized as thetherapeutic compound described herein. In another embodiment, compoundsdescribed herein contain one or more chiral centers. These compounds areprepared by any means, including stereoselective synthesis,enantioselective synthesis and/or separation of a mixture of enantiomersand/or diastereomers. Resolution of compounds and isomers thereof isachieved by any means including, by way of non-limiting example,chemical processes, enzymatic processes, fractional crystallization,distillation, and chromatography.

In one embodiment, the compounds of the invention may exist astautomers. All tautomers are included within the scope of the compoundspresented herein.

Compounds described herein also include isotopically-labeled compoundswherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes suitablefor inclusion in the compounds described herein include and are notlimited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O,¹⁷O, ¹⁸O, ³²P, and ³⁵S. In one embodiment, isotopically-labeledcompounds are useful in drug and/or substrate tissue distributionstudies. In another embodiment, substitution with heavier isotopes suchas deuterium affords greater metabolic stability (for example, increasedin vivo half-life or reduced dosage requirements). In yet anotherembodiment, substitution with positron emitting isotopes, such as ¹¹C,¹⁸F, ¹⁵O and ¹³N, is useful in Positron Emission Topography (PET)studies for examining substrate receptor occupancy. Isotopically-labeledcompounds are prepared by any suitable method or by processes using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed.

In one embodiment, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

The compounds described herein, and other related compounds havingdifferent substituents are synthesized using techniques and materialsdescribed herein and as described, for example, in Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (allof which are incorporated by reference for such disclosure). Generalmethods for the preparation of compound as described herein are modifiedby the use of appropriate reagents and conditions, for the introductionof the various moieties found in the formula as provided herein.

Compounds described herein are synthesized using any suitable proceduresstarting from compounds that are available from commercial sources, orare prepared using procedures described herein.

In one embodiment, reactive functional groups, such as hydroxyl, amino,imino, thio or carboxy groups, are protected in order to avoid theirunwanted participation in reactions. Protecting groups are used to blocksome or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. In another embodiment, each protective group is removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

Methods of the Invention

The invention provides a method of treating an HBV infection in anindividual in need thereof, comprising administering to the individual atherapeutically effective amount of a compound of the invention.

The invention also provides a method of eradicating an HBV infection inan individual in need thereof, comprising administering to theindividual a therapeutically effective amount of a compound of theinvention.

The invention also provides a method of reducing viral load associatedwith an HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of the invention.

The invention further provides a method of reducing reoccurrence of anHBV infection in an individual in need thereof, comprising administeringto the individual a therapeutically effective amount of a compound ofthe invention.

The invention further provides a method of inhibiting or reducing theformation or presence of HBV DNA-containing particles or HBVRNA-containing particles in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of the invention.

The invention also provides a method of reducing an adversephysiological impact of an HBV infection in an individual in needthereof, comprising administering to the individual a therapeuticallyeffective amount of a compound of the invention.

The invention further provides a method of reducing, slowing, orinhibiting an HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of the invention.

The invention also provides a method of inducing remission of hepaticinjury from an HBV infection in an individual in need thereof,comprising administering to the individual a therapeutically effectiveamount of a compound of the invention.

The invention further provides a method of reducing the physiologicalimpact of long-term antiviral therapy for HBV infection in an individualin need thereof, comprising administering to the individual atherapeutically effective amount of a compound of the invention.

The invention further provides a method of prophylactically treating anHBV infection in an individual in need thereof, wherein the individualis afflicted with a latent HBV infection, comprising administering tothe individual a therapeutically effective amount of a compound of theinvention.

In one embodiment, the methods described herein further compriseadministering at least one additional therapeutic agent selected fromthe group consisting of nucleotide/nucleoside analogs, entry inhibitors,fusion inhibitors, and any combination of these or other antiviralmechanisms. In another embodiment, the compound of the invention and theat least one additional therapeutic agent are co-formulated. In yetanother embodiment, the compound of the invention and the at least oneadditional therapeutic agent are co-administered.

In one embodiment, the individual is refractory to other therapeuticclasses of HBV drugs (e.g, HBV polymerase inhibitors, interferons, viralentry inhibitors, viral maturation inhibitors, literature-describedcapsid assembly modulators, antiviral compounds of distinct or unknownmechanism, and the like, or combinations thereof). In anotherembodiment, the method of the invention reduces viral load in anindividual suffering from an HBV infection to a greater extent or at afaster rate compared to the extent that other therapeutic classes of HBVdrugs reduce viral load in the individual.

In one embodiment, the administering of a compound of the invention, ora pharmaceutically acceptable salt thereof, allows for administering ofthe at least one additional therapeutic agent at a lower dose orfrequency as compared to the administering of the at least oneadditional therapeutic agent alone that is required to achieve similarresults in prophylactically treating an HBV infection in an individualin need thereof.

In one embodiment, the administering of a compound of the invention, ora pharmaceutically acceptable salt thereof, reduces the viral load inthe individual to a greater extent or at a faster rate compared to theadministering of a compound selected from the group consisting of an HBVpolymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, distinct capsid assembly modulator, antiviralcompounds of distinct or unknown mechanism, and any combination thereof.

In one embodiment, the method of the invention reduces viral load in anindividual suffering from an HBV infection, thus allowing lower doses orvarying regimens of combination therapies to be used.

In one embodiment, the method of the invention causes a lower incidenceof viral mutation and/or viral resistance compared to other classes ofHBV drugs, thereby allowing for long term therapy and minimizing theneed for changes in treatment regimens.

In one embodiment, the administering of a compound the invention, or apharmaceutically acceptable salt thereof, causes a lower incidence ofviral mutation and/or viral resistance than the administering of acompound selected from the group consisting of an HBV polymeraseinhibitor, interferon, viral entry inhibitor, viral maturationinhibitor, distinct capsid assembly modulator, antiviral compounds ofdistinct or unknown mechanism, and combination thereof.

In one embodiment, the method of the invention increases theseroconversion rate beyond that of current treatment regimens.

In one embodiment, the method of the invention increases and/ornormalizes and/or restores normal health, elicits full recovery ofnormal health, restores life expectancy, and/or resolves the viralinfection in the individual in need thereof.

In one embodiment, the method of the invention eliminates or decreasesthe number of HBV RNA particles that are released from HBV infectedcells thus enhancing, prolonging, or increasing the therapeutic benefitof the compounds of the invention.

In one embodiment, the method of the invention eradicates HBV from anindividual infected with HBV, thereby obviating the need for long termand/or life-long treatment, or shortening the duration of treatment,and/or allowing for reduction in dosing of other antiviral agents.

In another embodiment, the method of the invention further comprisesmonitoring the HBV viral load of the subject, and wherein the method iscarried out for a period of time such that the HBV virus isundetectable.

Accordingly, in one embodiment, provided herein is a method of treatingan HBV infection in an individual in need thereof, comprisingadministering to the individual a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound ofFormula II, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound ofFormula III, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound ofFormula IV, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound of Table1, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBVinfection in an individual in need thereof, comprising administering tothe individual a therapeutically effective amount of a compound of Table2, or a pharmaceutically acceptable salt thereof.

In an embodiment of any of the methods provided herein, the method canfurther comprise monitoring the HBV viral load of the subject, whereinthe method is carried out for a period of time such that the HBV virusis undetectable.

Combination Therapies

The compounds of the present invention are intended to be useful incombination with one or more additional compounds useful for treatingHBV infection. These additional compounds may comprise compounds of thepresent invention or compounds known to treat, prevent, or reduce thesymptoms or effects of HBV infection. Such compounds include but are notlimited to HBV polymerase inhibitors, interferons, viral entryinhibitors, viral maturation inhibitors, literature-described capsidassembly modulators, reverse transcriptase inhibitor, immunomodulatoryagents, a TLR-agonist, and other agents with distinct or unknownmechanisms that affect the HBV life cycle and/or affect the consequencesof HBV infection.

In non-limiting examples, the compounds of the invention may be used incombination with one or more drugs (or a salt thereof) selected from thegroup consisting of

HBV reverse transcriptase inhibitors, and DNA and RNA polymeraseinhibitors, including but not limited to: lamivudine (3TC, Zeffix,Heptovir, Epivir, and Epivir-HBV), entecavir (Baraclude, Entavir),adefovir dipivoxil (Hepsara, Preveon, bis-POM PMEA), tenofovirdisoproxil fumarate (Viread, TDF or PMPA);

interferons, including but not limited to interferon alpha (IFN-α),interferon beta (IFN-β), interferon lambda (IFN-λ), and interferon gamma(IFN-γ);

viral entry inhibitors;

viral maturation inhibitors;

literature-described capsid assembly modulators, such as, but notlimited to BAY 41-4109;

reverse transcriptase inhibitor;

an immunomodulatory agent such as a TLR-agonist; and

agents of distinct or unknown mechanism, such as but not limited toAT-61((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide),AT-130((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide),and similar analogs.

In one embodiment, the additional therapeutic agent is an interferon.The term “interferon” or “IFN” refers to any member the family of highlyhomologous species-specific proteins that inhibit viral replication andcellular proliferation, and modulate immune response. Human interferonsare grouped into three classes; Type I, which include interferon-alpha(IFN-α), interferon-beta (IFN-β), and interferon-omega (IFN-ω), Type II,which includes interferon-gamma (IFN-γ), and Type III, which includesinterferon-lambda (IFN-λ). Recombinant forms of interferons that havebeen developed and are commercially available are encompassed by theterm “interferon” as used herein. Subtypes of interferons, such aschemically modified or mutated interferons, are also encompassed by theterm “interferon” as used herein. Chemically modified interferonsinclude pegylated interferons and glycosylated interferons. Examples ofinterferons also include, but are not limited to, interferon-alpha-2a,interferon-alpha-2b, interferon-alpha-n1, interferon-beta-1a,interferon-beta-1b, interferon-lamda-1, interferon-lamda-2, andinterferon-lamda-3. Examples of pegylated interferons include pegylatedinterferon-alpha-2a and pegylated interferson alpha-2b.

Accordingly, in one embodiment, the compounds of Formula I, II, III, orIV, can be administered in combination with an interferon selected fromthe group consisting of interferon alpha (IFN-α), interferon beta(IFN-β), interferon lambda (IFN-λ), and interferon gamma (IFN-γ). In onespecific embodiment, the interferon is interferon-alpha-2a,interferon-alpha-2b, or interferon-alpha-n1. In another specificembodiment, the interferon-alpha-2a or interferon-alpha-2b is pegylated.In a preferred embodiment, the interferon-alpha-2a is pegylatedinterferon-alpha-2a (PEGASYS).

In another embodiment, the additional therapeutic agent is selected fromimmune modulator or immune stimulator therapies, which includesbiological agents belonging to the interferon class.

Further, the additional therapeutic agent may be an agent of distinct orunknown mechanism including agents that disrupt the function of otheressential viral protein(s) or host proteins required for HBV replicationor persistence.

In another embodiment, the additional therapeutic agent is an antiviralagent that blocks viral entry or maturation or targets the HBVpolymerase such as nucleoside or nucleotide or non-nucleos(t)idepolymerase inhibitors. In a further embodiment of the combinationtherapy, the reverse transcriptase inhibitor and/or DNA and/or RNApolymerase inhibitor is Zidovudine, Didanosine, Zalcitabine, ddA,Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine,Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir,ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir,Efavirenz, Nevirapine, Delavirdine, or Etravirine.

In an embodiment, the additional therapeutic agent is animmunomodulatory agent that induces a natural, limited immune responseleading to induction of immune responses against unrelated viruses. Inother words, the immunomodulatory agent can effect maturation of antigenpresenting cells, proliferation of T-cells and cytokine release (e.g.,IL-12, IL-18, IFN-alpha, -beta, and -gamma and TNF-alpha among others).

In a further embodiment, the additional therapeutic agent is a TLRmodulator or a TLR agonist, such as a TLR-7 agonist or TLR-9 agonist. Infurther embodiment of the combination therapy, the TLR-7 agonist isselected from the group consisting of SM360320(9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848 (methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).

In any of the methods provided herein, the method may further compriseadministering to the individual at least one HBV vaccine, a nucleosideHBV inhibitor, an interferon or any combination thereof. In anembodiment, the HBV vaccine is at least one of RECOMBIVAX HB, ENGERIX-B,ELOVAC B, GENEVAC-B, or SHANVAC B.

In another aspect, provided herein is method of treating an HBVinfection in an individual in need thereof, comprising reducing the HBVviral load by administering to the individual a therapeuticallyeffective amount of a compound of the invention alone or in combinationwith a reverse transcriptase inhibitor; and further administering to theindividual a therapeutically effective amount of HBV vaccine. Thereverse transcriptase inhibitor may be one of Zidovudine, Didanosine,Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine,Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir,valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA,cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.

For any combination therapy described herein, synergistic effect may becalculated, for example, using suitable methods such as theSigmoid-E_(max) equation (Holford & Scheiner, 19981, Clin.Pharmacokinet. 6: 429-453), the equation of Loewe additivity (Loewe &Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326) and themedian-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each equation referred to above may be applied to experimentaldata to generate a corresponding graph to aid in assessing the effectsof the drug combination. The corresponding graphs associated with theequations referred to above are the concentration-effect curve,isobologram curve and combination index curve, respectively.

In an embodiment of any of the methods of administering combinationtherapies provided herein, the method can further comprise monitoringthe HBV viral load of the subject, wherein the method is carried out fora period of time such that the HBV virus is undetectable.

Administration/Dosage/Formulations

In another aspect, provided herein is pharmaceutical compositioncomprising a compound of the invention, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

In particular, the selected dosage level will depend upon a variety offactors including the activity of the particular compound employed, thetime of administration, the rate of excretion of the compound, theduration of the treatment, other drugs, compounds or materials used incombination with the compound, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skillin the art may readily determine and prescribe the effective amount ofthe pharmaceutical composition required. For example, the physician orveterinarian could start doses of the compounds of the inventionemployed in the pharmaceutical composition at levels lower than thatrequired in order to achieve the desired therapeutic effect andgradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulatethe compound in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the patients tobe treated; each unit containing a predetermined quantity of therapeuticcompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical vehicle. The dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the therapeutic compound and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding/formulating such a therapeutic compound for thetreatment of HBV infection in a patient.

In one embodiment, the compositions of the invention are formulatedusing one or more pharmaceutically acceptable excipients or carriers. Inone embodiment, the pharmaceutical compositions of the inventioncomprise a therapeutically effective amount of a compound of theinvention and a pharmaceutically acceptable carrier.

In some embodiments, the dose of a compound of the invention is fromabout 1 mg to about 2,500 mg. In some embodiments, a dose of a compoundof the invention used in compositions described herein is less thanabout 10,000 mg, or less than about 8,000 mg, or less than about 6,000mg, or less than about 5,000 mg, or less than about 3,000 mg, or lessthan about 2,000 mg, or less than about 1,000 mg, or less than about 500mg, or less than about 200 mg, or less than about 50 mg. Similarly, insome embodiments, a dose of a second compound (i.e., another drug forHBV treatment) as described herein is less than about 1,000 mg, or lessthan about 800 mg, or less than about 600 mg, or less than about 500 mg,or less than about 400 mg, or less than about 300 mg, or less than about200 mg, or less than about 100 mg, or less than about 50 mg, or lessthan about 40 mg, or less than about 30 mg, or less than about 25 mg, orless than about 20 mg, or less than about 15 mg, or less than about 10mg, or less than about 5 mg, or less than about 2 mg, or less than about1 mg, or less than about 0.5 mg, and any and all whole or partialincrements thereof.

In one embodiment, the present invention is directed to a packagedpharmaceutical composition comprising a container holding atherapeutically effective amount of a compound of the invention, aloneor in combination with a second pharmaceutical agent; and instructionsfor using the compound to treat, prevent, or reduce one or more symptomsof HBV infection in a patient.

Routes of administration of any of the compositions of the inventioninclude oral, nasal, rectal, intravaginal, parenteral, buccal,sublingual or topical. The compounds for use in the invention may beformulated for administration by any suitable route, such as for oral orparenteral, for example, transdermal, transmucosal (e.g., sublingual,lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- andperivaginally), (intra)nasal and (trans)rectal), intravesical,intrapulmonary, intraduodenal, intragastrical, intrathecal,subcutaneous, intramuscular, intradermal, intra-arterial, intravenous,intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets,capsules, caplets, pills, gel caps, troches, dispersions, suspensions,solutions, syrups, granules, beads, transdermal patches, gels, powders,pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs,suppositories, liquid sprays for nasal or oral administration, drypowder or aerosolized formulations for inhalation, compositions andformulations for intravesical administration and the like. It should beunderstood that the formulations and compositions that would be usefulin the present invention are not limited to the particular formulationsand compositions that are described herein.

For oral application, particularly suitable are tablets, dragees,liquids, drops, suppositories, or capsules, caplets and gelcaps. Thecompositions intended for oral use may be prepared according to anymethod known in the art and such compositions may contain one or moreagents selected from the group consisting of inert, non-toxicpharmaceutically excipients that are suitable for the manufacture oftablets. Such excipients include, for example an inert diluent such aslactose; granulating and disintegrating agents such as cornstarch;binding agents such as starch; and lubricating agents such as magnesiumstearate. The tablets may be uncoated or they may be coated by knowntechniques for elegance or to delay the release of the activeingredients. Formulations for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertdiluent.

For parenteral administration, the compounds of the invention may beformulated for injection or infusion, for example, intravenous,intramuscular or subcutaneous injection or infusion, or foradministration in a bolus dose and/or continuous infusion. Suspensions,solutions or emulsions in an oily or aqueous vehicle, optionallycontaining other formulatory agents such as suspending, stabilizingand/or dispersing agents may be used.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents were considered to be within the scope of thisinvention and covered by the claims appended hereto. For example, itshould be understood, that modifications in reaction conditions,including but not limited to reaction times, reaction size/volume, andexperimental reagents, such as solvents, catalysts, pressures,atmospheric conditions, e.g., nitrogen atmosphere, andreducing/oxidizing agents, with art-recognized alternatives and using nomore than routine experimentation, are within the scope of the presentapplication.

It is to be understood that wherever values and ranges are providedherein, all values and ranges encompassed by these values and ranges,are meant to be encompassed within the scope of the present invention.Moreover, all values that fall within these ranges, as well as the upperor lower limits of a range of values, are also contemplated by thepresent application.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

EXAMPLES

The invention is now described with reference to the following Examples.These Examples are provided for the purpose of illustration only, andthe invention is not limited to these Examples, but rather encompassesall variations that are evident as a result of the teachings providedherein.

Example 1: Preparation of Compounds 010 and 059

Step 1: Preparation of Compound 3

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(1.00 g, 4.24 mmol, 1.00 Eq) and 2-phenoxyacetic acid (645.50 mg, 4.24mmol, 1.00 Eq) in DCM (40 mL), was added HATU (1.93 g, 5.09 mmol, 1.20Eq) and DIPEA (1.37 g, 10.60 mmol, 2.50 Eq) in one portion at 30° C.under N₂. The mixture was stirred at 30° C. for 12 hr. LCMS showed thereaction was completed. The mixture was poured into water (50 mL) andstirred for 2 min. The aqueous phase was extracted with DCM (20 mL*2).The combined organic phase was washed with saturated brine (20 mL*2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography (Petroleum ether/Ethylacetate=3/1) to afford2-phenoxy-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone (1.30 g, 3.90 mmol, 91.97% yield) as yellow solid. LCMS: 334[M+I].

Preparation of Compounds 010 and 059

To a mixture of2-phenoxy-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine(5-yl)ethanone (150.00 mg, 449.94 umol, 1.00 Eq) in DMF (10 mC), wasadded Na (36.00 mg, 899.88 umol, 2.00 Eq) in one portion at 0° C. underN. The mixture was stirred at 0° C. for 0.5 hr, then MeI (191.59 mg,1.35 mmol, 3.00 Eq) was added to the mixture at 0° C. The mixture washeated to 30° C. and stirred for 12 hours. LCMS showed the reaction wascompleted. The mixture was quenched with water. The aqueous phase wasextracted with ethyl acetate (10 mL*2). The combined organic phase waswashed with saturated brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified bypre-HPLC(FA) to afford a region-isomeric mixture (85.34 mg, 245.65 umol,54.60% yield) as yellow solid. The yellow solid was separated by SFC toafford1-(1-methyl-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone(21.34 mg, 61.43 umol) and1-(2-methyl-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone(32.11 mg, 92.43 umol). Characterization of Compound 010: ¹H NMR (400MHz, Methanol-d₄) δ 7.56-7.66 (m, 2H), 7.43 (s, 5H), 6.84-7.04 (m, 3H),4.89-4.92 (m, 1H), 4.85 (s, 1H), 4.76-4.80 (m, 2H), 3.87-4.00 (m, 2H),3.74-3.82 (m, 3H), 2.73-2.95 (m, 2H). LCMS: 348 [M+1]. Characterizationof Compound 059: ¹H NMR (400 MHz, Methanol-d₄) δ 7.39-7.67 (m, 5H),7.19-7.33 (m, 2H), 6.83-7.02 (m, 3H), 4.88-4.90 (m, 2H), 4.54-4.61 (m,2H), 3.84-4.00 (m, 2H), 3.77 (s, 3H), 2.71-2.92 (m, 2H). LCMS: 348[M+1].

Example 2: Preparation of Compounds 011 and 060

To a mixture of2-phenoxy-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone (150.00 mg, 449.94 umol, 1.00 Eq) in DMF (10 mL), was added NaH(36.00 mg, 899.88 umol, 2.00 Eq) in one portion at 0° C. under N₂. Themixture was stirred at 0° C. for 0.5 hr, then iodoethane (210.53 mg,1.35 mmol, 3.00 Eq) was added to the mixture at 0° C. The mixture washeated to 30° C. and stirred for 12 hours. LCMS showed the reaction wascompleted. The mixture was quenched with water (5 mL) and stirred for 5min. The aqueous phase was extracted with ethyl acetate (15 mL*2). Thecombined organic phase was washed with saturated brine (15 mL*2), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by pre-HPLC (FA) to afford1-(1-ethyl-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone(71.20 mg, 196.99 umol, 43.78% yield) and1-(2-ethyl-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone(21.49 mg, 59.46 umol, 13.21% yield) as white solid.

Charactertization of Compound 011: ¹H NMR (400 MHz, Methanol-d₄) δ7.57-7.66 (m, 2H), 7.38-7.50 (m, 2H), 7.15-7.38 (m, 3H), 6.83-7.05 (m,3H), 4.91 (s, 1H), 4.83-4.86 (m, 1H), 4.75-4.81 (m, 2H), 4.05-4.18 (m,2H), 3.85-4.03 (m, 2H), 2.87-2.96 (m, 1H), 2.75-2.83 (m, 1H), 1.40 (s,3H). LCMS: 362 [M+1].

Characterization of Compound 060: ¹H NMR (400 MHz, Methanol-d₄) δ7.44-7.59 (m, 3H), 7.37-7.44 (m, 2H), 7.19-7.33 (m, 2H), 6.84-7.02 (m,3H), 4.89 (br. s., 2H), 4.51-4.62 (m, 2H), 4.08 (d, J=7.28 Hz, 2H), 3.89(s, 2H), 2.85-2.91 (m, 1H), 2.74-2.81 (m, 1H), 1.31 (t, J=7.22 Hz, 3H).LCMS: 362 [M+1].

Example 3: Preparation of Compounds 012 and 061

To a mixture of2-phenoxy-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)ethanone(150.00 mg, 449.94 umol, 1.00 Eq) in DMF (10 mL), was added NaH (36.00mg, 899.88 umol, 2.00 Eq) in one portion at 0° C. under N₂. The mixturewas stirred at 0° C. for 0.5 hr, then 2-iodopropane (229.46 mg, 1.35mmol, 3.00 Eq) was added to the mixture, the mixture was heated to 30°C. and stirred for 12 hours. LCMS showed the reaction was completed. Themixture was poured into water (10 mL) and stirred for 5 min. The aqueousphase was extracted with ethyl acetate (20 mL*2). The combined organicphase was washed with saturated brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bypre-HPLC(FA) to afford 1-(1-isopropyl-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c] pyridin-5-yl)-2-phenoxy-ethanone (22.18 mg, 59.07 umol, 13.13%yield) and1-(2-isopropyl-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone(54.13 mg, 144.17 umol, 32.04% yield) as yellow solid. Characterizationof Compound 012: ¹H NMR (400 MHz, Methanol-d₄) δ 7.57-7.69 (m, 2H),7.39-7.49 (m, 2H), 7.17-7.38 (m, 3H), 6.84-7.06 (m, 3H), 4.91 (s, 2H),4.75-4.81 (m, 2H), 4.40-4.58 (m, 1H), 3.84-4.04 (m, 2H), 2.75-3.00 (m,2H), 1.49 (d, J=6.53 Hz, 6H). LCMS: 376 [M+1]. Characterization ofCompound 061: ¹H NMR (400 MHz, Methanol-d₄) δ 7.43-7.60 (m, 3H),7.34-7.41 (m, 2H), 7.18-7.33 (m, 2H), 6.82-7.02 (m, 3H), 4.89 (br. s.,2H), 4.43-4.63 (m, 3H), 3.81-4.01 (m, 2H), 2.74-2.94 (m, 2H), 1.41 (d,J=6.65 Hz, 6H). LCMS: 376 [M+1].

Example 4: Preparation of Compounds 013, 056, 062, and 063

Step 1: Preparation of Compound 3 and Compound 3-isomer

To a mixture of2-phenoxy-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone(400.00 mg, 1.20 mmol, 1.00 Eq) in DMF (10 mL), was added NaH (95.99 mg,2.40 mmol, 2.00 Eq) in one portion at 0° C. under N₂. The mixture wasstirred at 0° C. for 1 hr, 10 then 3-bromoprop-1-ene (362.94 mg, 3.00mmol, 2.50 Eq) was added to the mixture, the mixture was heated to 30 HCand stirred for 12 hours. LCMS showed the reaction was completed. Themixture was poured into ice-water (w/w=1/1) (20 mL) and stirred for 5min. The aqueous phase was extracted with ethyl acetate (40 mL*2). Thecombined organic phase was washed with saturated brine (30 L*2, driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by silica gel chromatography (Petroleum ether/Ethylacetate=3/1) to afford1-(1-allyl-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone(330.00 mg, 883.65 umol, 73.64% yield) and1-(2-allyl-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone(120.00 mg, 267.77 umol, 22.31% yield) as yellow solid. LCMS: 374 [M+1].

Preparation of Compound 056

To a solution of1-(1-allyl-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone(100.00 mg, 267.77 umol, 1.00 Eq) in MeOH (10 mL) was added Pd—C (10%,20.00 mg) under N₂. The suspension was degassed under vacuum and purgedwith H₂ several times. The mixture was stirred under H₂ (15 psi) at 30°C. for 12 hours. LCMS showed the starting material was consumedcompletely. The reaction mixture was filtered and the filter wasconcentrated. The crude product was purified by pre-HPLC(FA) to give2-phenoxy-1-(3-phenyl-1-propyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone(45.32 mg, 120.71 umol, 45.08% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 7.56-7.70 (m, 2H), 7.35-7.48 (m, 2H), 7.20-7.34 (m, 3H),6.85-7.00 (m, 3H), 4.87-5.01 (m, 2H), 4.60-4.77 (m, 2H), 3.89-4.07 (m,2H), 3.67-3.85 (m, 2H), 2.80-2.95 (m, 1H), 2.65-2.76 (m, 1H), 1.69-1.84(m, 2H), 0.86 (t, J=7.34 Hz, 3H). LCMS: 376 [M+1].

Preparation of Compound 063

To a solution of 1-(2-allyl-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone (50.00 mg, 133.89 umol, 1.00 Eq)in MeOH (10 mL) was added Pd—C(10%, 5 mg) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 30° C. for 10 hours. LCMS showed thestarting material was consumed completely. The reaction mixture wasfiltered and the filter was concentrated. The crude product was purifiedby pre-HPLC(FA) to give2-phenoxy-1-(3-phenyl-2-propyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone(25.34 mg, 67.49 umol, 50.41% yield) as white solid. LCMS: 376 [M+1].

Preparation of Compound 013

To a mixture of1-(1-allyl-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone(150.00 mg, 401.66 umol, 1.00 Eq) in THF (10 mL) and H2O (2 mL), wasadded NaIO4 (189.00 mg, 883.65 umol, 2.20 Eq) and OsO4 (10.21 mg, 40.17umol, 0.10 Eq) in one portion under N₂. The mixture was stirred at 30°C. for 5 hr. The mixture was washed with saturated Na₂SO₃ (20 mL*2), Theaqueous phase was extracted with ethyl acetate (10 mL*2). The combinedorganic phase was dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was diluted in EtOH (10 mL), NaBH4 (15.20 mg,401.66 umol, 1.00 Eq) was added to the mixture. The mixture was stirredat 30° C. for 5 hr. LCMS showed the reaction was completed. The mixturewas poured into water (20 mL) and stirred for 5 min. The aqueous phasewas extracted with ethyl acetate (15 mL*2). The combined organic phasewas washed with saturated brine (15 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified bypre-HPLC(FA) to afford1-[1-(2-hydroxyethyl)-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-2-phenoxy-ethanone(45.32 mg, 120.07 umol, 29.89% yield) as white solid. LCMS: 378 [M+1].

Preparation of Compound 062

To a mixture of1-(2-allyl-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone(70.00 mg, 187.44 umol, 1.00 Eq) in THF (10 mL) and H2O (2 mL), wasadded NaIO4 (88.20 mg, 412.37 umol, 2.20 Eq) and OsO4 (4.77 mg, 18.74umol, 0.10 Eq) in one portion under N₂. The mixture was stirred at 30°C. for 5 hr. The mixture was washed with saturated Na₂SO₃ (20 mL*2), Theaqueous phase was extracted with ethyl acetate (10 mL*2). The combinedorganic phase was dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was diluted in EtOH (10 mL), NaBH4 (8.51 mg,224.93 umol, 1.20 Eq) was added to the mixture. The mixture was stirredat 30° C. for 5 hr. LCMS showed the reaction was completed. The mixturewas poured into water (20 mL) and stirred for 5 min. The aqueous phasewas extracted with ethyl acetate (15 mL*2). The combined organic phasewas washed with saturated brine (15 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified bypre-HPLC(FA) to afford1-[2-(2-hydroxyethyl)-3-phenyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-2-phenoxy-ethanone(18.24 mg, 48.33 umol, 25.78% yield) as white solid. LCMS: 378 [M+1].

Example 5: Preparation of Compound 024

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(150.00 mg, 636.38 umol, 1.00 Eq) in DCM (5 mL), was added CbzCl (130.27mg, 763.66 umol, 1.20 Eq) and TEA (193.19 mg, 1.91 mmol, 3.00 Eq) in oneportion under N₂. The mixture was stirred at 30° C. for 12 hr. LCMSshowed the reaction was completed. The mixture was washed with saturatedbrine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by pre-HPLC (FA) to afford benzyl3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (48.97mg, 146.89 umol, 23.08% yield) as white solid. ¹H NMR (400 MHz,Methanol-d₄) 7.50-7.64 (m, 2H), 7.41-7.50 (m, 2H), 7.24-7.41 (m, 6H),5.12-5.22 (m, 2H), 4.69-4.77 (m, 2H), 3.78-3.89 (m, 2H), 2.74-2.85 (m,2H). LCMS: 334 [M+1].

Example 6: Preparation of Compound 016

Step 1: Preparation of Compound 2

To a mixture of 1-phenylethanol (2.00 g, 16.37 mmol, 1.00 eq) and Py(3.24 g, 40.93 mmol, 2.50 eq) in DCM (75.00 mL), was added(4-nitrophenyl) carbonochloridate (3.30 g, 16.37 mmol, 1.00 eq) in DCM(75.00 mL) drop-wise at 0° C. under N₂. The mixture was stirred at 0° C.for 1 hr, then heated to 30° C. and stirred for 12 hours. TLC showed thereaction was completed. The mixture was poured into water (30 mL) andstirred for 5 min. The aqueous phase was extracted with ethyl acetate(20 mL*2). The combined organic phase was washed with saturated brine(20 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum. The residue was purified by silica gel chromatography (Petroleumether/Ethyl acetate=10/1) to afford (4-nitrophenyl) 1-phenylethylcarbonate (2.90 g, 10.10 mmol, 61.67% yield) as yellow solid. LCMS: 288[M+1].

Preparation of Compound 016

To a mixture of (4-nitrophenyl) 1-phenylethyl carbonate (150.00 mg,522.16 umol, 1.00 eq) and 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (123.08 mg, 522.16 umol, 1.00 eq) in MeCN (10.00 mL),was added TEA (158.51 mg, 1.57 mmol, 3.00 eq) in one portion at 30° C.under N₂. The mixture was stirred at 30° C. for 5 hours. LCMS showed thereaction was completed. The mixture was poured into water (10 mL) andstirred for 5 min. The aqueous phase was extracted with ethyl acetate(10 mL*2). The combined organic phase was washed with saturated brine(10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum. The residue was purified by pre-HPLC(FA) to afford 1-phenylethyl3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (54.40mg, 156.59 umol, 29.99% yield) as white solid. LCMS: 348 [M+1].

Example 7: Preparation of Compounds 025-030 and 057

Preparation of Compound 025

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 Eq) and 2-phenylacetic acid (57.76 mg,424.25 umol, 1.00 Eq) in DCM (10 mL), was added HATU (241.97 mg, 636.38umol, 1.50 Eq) and DIPEA (137.08 mg, 1.06 mmol, 2.50 Eq) in one portionat 30° C. under N₂. The mixture was stirred at 30° C. for 8 hr. LCMSshowed the reaction was completed. The mixture was poured into water (20mL) and stirred for 5 min. The aqueous phase was extracted with DCM (20mL*2). The combined organic phase was washed with saturated brine (20mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by pre-HPLC (FA) to afford 2-phenyl-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone (32.58 mg,102.65 umol, 24.20% yield) as white solid. LCMS: 318 [M+1].

Preparation of Compound 026

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 Eq) and 2-hydroxy-2-phenyl-acetic acid(64.55 mg, 424.25 umol, 1.00 Eq) in DCM (10 mL), was added HATU (241.97mg, 636.38 umol, 1.50 Eq) and DIPEA (137.08 mg, 1.06 mmol, 2.50 Eq) inone portion at 30° C. under N₂. The mixture was stirred at 30° C. for 8hr. LCMS showed the reaction was completed. The mixture was poured intowater (20 mL) and stirred for 5 min. The aqueous phase was extractedwith DCM (20 mL*2). The combined organic phase was washed with saturatedbrine (20 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by pre-HPLC (FA) to afford2-hydroxy-2-phenyl-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone(46.19 mg, 138.55 umol, 32.66% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) 7.13-7.69 (m, 10H), 5.75 (d, J=6.53 Hz, 1H), 5.51 (br. s., 1H),4.62-4.83 (m, 2H), 3.74 (br. s., 3H), 2.67 (br. s., 1H), 2.15 (d,J=15.18 Hz, 1H). LCMS: 334 [M+1].

Preparation of Compound 027

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg 424.25 umol, 1.00 Eq) and 3-phenylpropanoic acid (63.71 mg,424.25 umol, 1.00 Eq) in DCM (10 mL), was added HATU (241.97 mg, 636.38umol, 1.50 Eq) and DIPEA (137.08 mg, 1.06 mmol, 2.50 Eq) at 30° C. Themixture was stirred at 30° C. for 14 hr. LCMS showed the reaction wascompleted. The mixture was poured into water (20 mL) and stirred for 5min. The aqueous phase was extracted with DCM (20 mL*2). The combinedorganic phase was washed with saturated brine (20 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by pre-HPLC(FA) to afford3-phenyl-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)propan-1-one(24.76 mg, 74.71 umol, 17.61% yield) as white solid. LCMS: 332 [M+1].

Preparation of Compound 028

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 Eq) and 2-hydroxy-3-phenyl-propanoic acid(70.50 mg, 424.25 umol, 1.00 Eq), was added HATU (241.97 mg, 636.38umol, 1.50 Eq) and DIPEA (137.08 mg, 1.06 mmol, 2.50 Eq) at 30° C. Themixture was stirred at 30° C. for 15 hr. LCMS showed the reaction wascompleted. The mixture was poured into water (20 mL) and stirred for 5min. The aqueous phase was extracted with DCM (20 mL*2). The combinedorganic phase was washed with saturated brine (20 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by pre-HPLC (FA) to afford2-hydroxy-3-phenyl-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)propan-1-one(58.00 mg, 166.95 umol, 39.35% yield) as white solid. LCMS: 348 [M+1].

Preparation of Compound 029

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 Eq) and 3-hydroxy-3-phenyl-propanoic acid(70.50 mg, 424.25 umol, 1.00 Eq) in DCM (10 mL) was added HATU (241.97mg, 636.38 umol, 1.50 Eq) and DIPEA (137.08 mg, 1.06 mmol, 2.50 Eq) at30° C. The mixture was stirred at 30° C. for 15 hr. LCMS showed thereaction was completed. The mixture was poured into water (20 mL) andstirred for 5 min. The aqueous phase was extracted with DCM (20 mL*2).The combined organic phase was washed with saturated brine (20 mL*2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by pre-HPLC (FA) to afford3-hydroxy-3-phenyl-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)propan-1-one (95.00mg, 273.45 umol, 64.46% yield) as white solid. LCMS: 348 [M+1].

Preparation of Compound 030

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 Eq) and 2-phenylcyclopropanecarboxylicacid (68.80 mg, 424.25 umol, 1.00 Eq) in DCM (10 mL), was added DIPEA(137.08 mg, 1.06 mmol, 2.50 Eq) and HATU (241.97 mg, 636.38 umol, 1.50Eq) in one portion at 30° C. under N₂. The mixture was stirred at 30° C.for 4 hr. LCMS showed the reaction was completed. The mixture was pouredinto water (20 mL) and stirred for 5 min. The aqueous phase wasextracted with DCM (10 mL*2). The combined organic phase was washed withsaturated brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by pre-HPLC (FA) toafford(2-phenylcyclopropyl)-(3-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)methanone (27.92 mg, 81.30 umol, 19.16% yield) as white solid. ¹H NMR (400MHz, DMSO-d₆) 7.11-7.63 (m, 10H), 4.88 (d, J=14.56 Hz, 1H), 4.72 (s,1H), 3.67-3.99 (m, 2H), 2.63-2.86 (m, 2H), 2.27-2.47 (m, 2H), 1.43 (td,J=8.97, 4.52 Hz, 1H), 1.18-1.28 (m, 1H). LCMS: 344 [M+1].

Preparation of Compound 057

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 Eq) and (E)-3-phenylprop-2-enoic acid(62.86 mg, 424.25 umol, 1.00 Eq) in DCM (10 mL), was added HATU (241.97mg, 636.38 umol, 1.50 Eq) and DIPEA (137.08 mg, 1.06 mmol, 2.50 Eq) at30° C. The mixture was stirred at 30° C. for 5 hr. LCMS showed thereaction was completed. The mixture was poured into water (20 mL) andstirred for 5 min. The aqueous phase was extracted with DCM (20 mL*2).The combined organic phase was washed with saturated brine (20 mL*2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by pre-HPLC (FA) to afford(E)-3-phenyl-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)prop-2-en-1-one(61.85 mg, 187.77 umol, 44.26% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) 12.63-13.14 (m, 1H), 7.32-7.80 (m, 12H), 4.75-5.00 (m, 2H),3.86-4.06 (m, 2H), 2.67-2.90 (m, 2H). LCMS: 330 [M+1].

Example 8: Preparation of Compounds 017 Through 023

Preparation of Compound 017

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 Eq) and phenylmethanamine (45.46 mg,424.25 umol, 1.00 Eq) in DCM (10 mL), was added TEA (51.52 mg, 509.10umol, 1.20 Eq) and CDI (68.79 mg, 424.25 umol, 1.00 Eq) at 30° C. Themixture was stirred at 30° C. for 5 hr. LCMS showed the reaction wascompleted. The mixture was poured into water (20 mL) and stirred for 5min. The aqueous phase was extracted with DCM (20 mL*2). The combinedorganic phase was washed with saturated brine (20 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by pre-HPLC (FA) to affordN-benzyl-3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(29.09 mg, 87.52 umol, 20.63% yield) as white solid. LCMS: 333 [M+1].

Preparation of Compound 018

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 Eq) and 1-phenylethanamine (51.41 mg,424.25 umol, 1.00 Eq) in DCM (10 mL), was added TEA (51.52 mg, 509.10umol, 1.20 Eq) and CDI (68.79 mg, 424.25 umol, 1.00 Eq) at 30° C. Themixture was stirred at 30° C. for 14 hr. LCMS showed the reaction wascompleted. The mixture was poured into water (20 mL) and stirred for 5min. The aqueous phase was extracted with DCM (20 mL*2). The combinedorganic phase was washed with saturated brine (20 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by pre-HPLC (FA) to afford3-phenyl-N-(1-phenylethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (39.91 mg, 115.21 umol, 27.16% yield) aswhite solid. LCMS: 347 [M+1].

Preparation of Compound 019

To a mixture of N-methyl-1-phenyl-methanamine (51.41 mg, 424.25 umol,1.00 Eq) and TEA (214.65 mg, 2.12 mmol, 5.00 Eq) in DCM (15 mL), wasadded TRIPHOSGENE (50.36 mg, 169.70 umol, 0.40 Eq) at 0° C. under N₂.The mixture was stirred at 0° C. for 5 min, then added3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (100.00 mg,424.25 umol, 1.00 Eq) and stirred at 0° C. for 2 hours. LCMS showed thereaction was completed. The mixture was poured into water (20 mL) andstirred for 5 min. The aqueous phase was extracted with DCM (20 mL*2).The combined organic phase was washed with saturated brine (20 mL*2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by pre-HPLC (FA) to affordN-benzyl-N-methyl-3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (23.51 mg, 67.87 umol, 16.00% yield) aswhite solid. LCMS: 347 [M+1].

Preparation of Compound 020

Step 1: Preparation of Compound 5:

To a mixture of 1-phenylethanone (1.00 g, 8.32 mmol, 1.00 eq) andTitanium ethoxide (3.80 g, 16.64 mmol, 2.00 eq) in MeOH (15 mL), wasadded methanamine (2.58 g, 83.20 mmol, 10.00 eq) at 30° C. under N₂. Themixture was stirred at 30° C. for 5 hr, then added NaBH₄ (472.12 mg,12.48 mmol, 1.50 eq) at 0° C. under N₂ and stirred for 10 min. Themixture was heated to 30° C. and stirred for 19 hours. LCMS showed thereaction was completed. The mixture was added water (20 mL) in oneportion and stirred for 10 min. The aqueous phase was extracted with EA(20 mL*2). The combined organic phase was washed with saturated brine(20 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum to afford N-methyl-1-phenyl-ethanamine (700.00 mg, crude) asyellow oil. The crude product was used for next step directly withoutpurification. LCMS: 136 [M+1].

Step 2: Preparation of Compound 020:

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 Eq) and phenol (39.93 mg, 424.25 umol,1.00 Eq) in DCM (10 mL), was added TEA (51.52 mg, 509.10 umol, 1.20 Eq)and CDI (68.79 mg, 424.25 umol, 1.00 Eq) at 30° C. The mixture wasstirred at 30° C. for 8 hr. LCMS showed the reaction was completed. Themixture was poured into water (20 mL) and stirred for 5 min. The aqueousphase was extracted with DCM (20 mL*2). The combined organic phase waswashed with saturated brine (20 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified bypre-HPLC (FA) to affordphenyl3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(42.83 mg, 134.11 umol, 31.61% yield) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) ppm 7.11-7.66 (m, 10H), 5.20 (d, J=7.15 Hz, 1H), 4.42-4.58(m, 2H), 3.61 (q, J=5.98 Hz, 2H), 2.89 (t, J=5.58 Hz, 2H), 2.65 (s, 3H),1.57 (d, J=7.03 Hz, 3H). LCMS: 361 [M+1].

Preparation of Compound 021

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 Eq) and phenol (39.93 mg, 424.25 umol,1.00 Eq) in DCM (10 mL), was added TEA (51.52 mg, 509.10 umol, 1.20 Eq)and CDI (68.79 mg, 424.25 umol, 1.00 Eq) at 30° C. The mixture wasstirred at 30° C. for 8 hr. LCMS showed the reaction was completed. Themixture was poured into water (20 mL) and stirred for 5 min. The aqueousphase was extracted with DCM (20 mL*2). The combined organic phase waswashed with saturated brine (20 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified bypre-HPLC (FA) to affordphenyl3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(42.83 mg, 134.11 umol, 31.61% yield) as white solid. LCMS: 320 [M+1].

Preparation of Compound 022

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 Eq) and aniline (39.51 mg, 424.25 umol,1.00 Eq) in DCM (10 mL), was added TEA (51.52 mg, 509.10 umol, 1.20 Eq)and CDI (68.79 mg, 424.25 umol, 1.00 Eq) at 30° C. The mixture wasstirred at 30° C. for 8 hr. LCMS showed the reaction was completed. Themixture was poured into water (20 mL) and stirred for 5 min. The aqueousphase was extracted with DCM (20 mL*2). The combined organic phase waswashed with saturated brine (20 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified bypre-HPLC (FA) to affordN,3-diphenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(20.23 mg, 63.54 umol, 14.98% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) ppm 12.58-13.11 (m, 1H), 8.68 (s, 1H), 7.65 (br. s., 2H), 7.44(d, J=7.53 Hz, 5H), 7.23 (t, J=7.97 Hz, 2H), 6.90-6.97 (m, 1H), 4.72 (s,2H), 3.78 (t, J=5.33 Hz, 2H), 2.76 (br. s., 2H). LCMS: 319 [M+1].

Preparation of Compound 023

To a mixture of N-methylaniline (45.46 mg, 424.25 umol, 1.00 Eq) and TEA(214.65 mg, 2.12 mmol, 5.00 Eq) in DCM (15 mL), was added triphosgene(50.36 mg, 169.70 umol, 0.40 Eq) at 0° C. under N₂. The mixture wasstirred at 0° C. for 5 min, then added3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (100.00 mg,424.25 umol, 1.00 Eq) and stirred at 0° C. for 2 hours. LCMS showed thereaction was completed. The mixture was poured into water (20 mL) andstirred for 5 min. The aqueous phase was extracted with DCM (20 mL*2).The combined organic phase was washed with saturated brine (20 mL*2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by pre-HPLC (FA) to affordN-methyl-N,3-diphenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(32.10 mg, 96.57 umol, 22.76% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) ppm 12.47-13.04 (m, 1H), 7.38 (dd, J=16.00, 8.09 Hz, 7H),7.10-7.22 (m, 3H), 4.28 (s, 2H), 3.45 (d, J=5.52 Hz, 2H), 3.11 (s, 3H),2.38 (br. s., 2H). LCMS: 333 [M+1].

Example 9: Preparation of Compound 014

Step 1: Preparation of Compound 3

To a mixture of methyl 2-bromopropanoate (2.00 g, 11.98 mmol, 1.00 Eq)and phenol (1.13 g, 11.98 mmol, 1.00 Eq) in ACETONE (30 mL), was addedK₂CO₃ (2.48 g, 17.97 mmol, 1.50 Eq) at 30° C. The mixture was stirred at30° C. for 5 hr. LCMS showed the reaction was completed. The mixture wasconcentrated in reduced pressure at 45° C. The residue was poured intowater (50 mL) and stirred for 5 min. The aqueous phase was extractedwith ethyl acetate (50 mL*2). The combined organic phase was washed withsaturated brine (50 mL*2), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum to afford methyl 2-phenoxypropanoate (3.30 g,crude). The crude product was used for next step directly withoutpurification. LCMS: 181 [M+1].

Step 2: Preparation of Compound 4

To a mixture of methyl 2-phenoxypropanoate (3.30 g, 18.31 mmol, 1.00 Eq)and LiOH (877.05 mg, 36.62 mmol, 2.00 Eq) in THF (50 mL). The mixturewas stirred at 30° C. for 15 hr. TLC showed the reaction was completed.The mixture was poured into water (100 mL) and stirred for 10 min, andacidified with diluted hydrochloride acid, then the aqueous phase wasextracted with ethyl acetate (50 mL*3). The combined organic phase waswashed with saturated brine (50 mL*3), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum to afford 2-phenoxypropanoic acid(1.03 g, 6.20 mmol, 33.85% yield).

Preparation of Compound 014

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 Eq) and 2-phenoxypropanoic acid (70.50 mg,424.25 umol, 1.00 Eq) in DCM (10 mL) was added HATU (241.97 mg, 636.38umol, 1.50 Eq) and DIPEA (137.08 mg, 1.06 mmol, 2.50 Eq) at 30° C. Themixture was stirred at 30° C. for 15 hr. LCMS showed the reaction wascompleted. The mixture was poured into water (20 mL) and stirred for 5min. The aqueous phase was extracted with DCM (20 mL*2). The combinedorganic phase was washed with saturated brine (20 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by pre-HPLC (FA) to afford2-phenoxy-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)propan-1-one(96.00 mg, 276.33 umol, 65.13% yield) as white solid. LCMS: 348 [M+1].

Example 10: Preparation of Compound 015

Step 1: Preparation of Compound 3

To a mixture of methyl 2-bromo-2-methyl-propanoate (2.00 g, 11.05 mmol,1.00 Eq) and phenol (1.04 g, 11.05 mmol, 1.00 Eq) in ACETONE (30 mL),was added K2CO3 (2.29 g, 16.58 mmol, 1.50 Eq) at 30° C. Then heated to60° C. and stirred for 5 hours. LCMS showed the reaction was completed.The mixture was cooled to 30° C. and concentrated in reduced pressure at45° C. The residue was poured into water (50 mL) and stirred for 5 min.The aqueous phase was extracted with ethyl acetate (50 mL*2). Thecombined organic phase was washed with saturated brine (50 mL*2), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum to affordmethyl 2-methyl-2-phenoxy-propanoate (1.50 g, crude) as yellow oil. Thecrude product was used for next step directly without purification.LCMS: 195 [M+1].

Step 2: Preparation of Compound 4

To a mixture of methyl 2-methyl-2-phenoxy-propanoate (1.50 g, 7.72 mmol,1.00 Eq) and LiOH (369.79 mg, 15.44 mmol, 2.00 Eq) in THF (50 mL) andH2O (10 mL). The mixture was stirred at 30° C. for 15 hr. TLC showed thereaction was completed. The mixture was poured into water (100 mL) andstirred for 10 min. Acidify the aqueous phase with diluted hydrochlorideacid, then the aqueous phase was extracted with ethyl acetate (50 mL*3).The combined organic phase was washed with saturated brine (50 mL*3),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum toafford 2-methyl-2-phenoxy-propanoic acid (850.00 mg, 4.72 mmol, 61.10%yield).

Preparation of Compound 015

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 eq) and 2-methyl-2-phenoxy-propanoic acid(76.45 mg, 424.25 umol, 1.00 eq) in DCM (10 mL), was added HATU (241.97mg, 636.38 umol, 1.50 eq) and DIPEA (137.08 mg, 1.06 mmol, 2.50 eq) at30° C. The mixture was stirred at 30° C. for 18 hr. LCMS showed thereaction was completed. The mixture was poured into water (20 mL) andstirred for 5 min. The aqueous phase was extracted with DCM (20 mL*2).The combined organic phase was washed with saturated brine (20 mL*2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by pre-HPLC (FA) to afford2-methyl-2-phenoxy-1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)propan-1-one(21.30 mg, 58.93 umol, 13.89% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) ppm 7.59 (d, J=7.40 Hz, 1H), 7.43-7.52 (m, 3H), 7.34 (t, J=7.03Hz, 1H), 7.25 (t, J=7.53 Hz, 1H), 7.11-7.18 (m, 1H), 6.77-6.99 (m, 2H),6.68 (d, J=7.65 Hz, 1H), 5.02 (br. s., 1H), 4.74 (br. s., 1H), 4.08 (br.s., 2H), 3.81 (br. s., 2H), 1.42-1.64 (m, 6H). LCMS: 362 [M+1].

Example 11: Preparation of Compound 067

To a mixture of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(100.00 mg, 424.25 umol, 1.00 eq) and methanamine hydrochloride (28.64mg, 424.25 umol, 1.00 eq) in DCM (15.00 mL), was added TEA (429.30 mg,4.24 mmol, 10.00 eq) at 0° C. under N₂. The mixture was stirred at 0° C.for 5 min, then added TRIPHOSGENE (50.36 mg, 169.70 umol, 0.40 eq) andheated to 30° C. for 15 hours. LCMS showed the reaction was completed.The mixture was poured into water (20 mL) and stirred for 5 min. Theaqueous phase was extracted with DCM (20 mL*2). The combined organicphase was washed with saturated brine (20 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bypre-HPLC (FA) to afford N-methyl-3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxamide (11.68 mg, 45.57 umol, 10.74%yield) as white solid. LCMS: 257 [M+1].

Example 12: Preparation of Compounds 111, 112, 113, and 114

Condition 1:

To a mixture of triphosgene (0.6 eq) and amine (1.05 eq) in DCM (5 mL)was added Et₃N (1.0 eq) in one portion at 0° C. The mixture was stirredat 0-10° C. for 20 min, and then added intermediate 1 (1.0 eq) and Et₃N(2.2 eq) at 0° C. The mixture was stirred at 0-10° C. for 5 min. Thedesired product was detected by LCMS. The reaction mixture wasconcentrated under reduced pressure. The residue was purified bypre-HPLC to give the desired products.

Condition 2:

To a mixture of amine (1.05 eq) in DMF (5.00 mL) was added CDI (1.05 eq)in one portion at 25° C. The mixture was stirred for 20 min, and thenadded intermediate 1 (1.0 eq) and Et₃N (2.2 eq). The mixture was stirredfor 16-48 hours (25° C.-40° C.). The desired product was detected byLCMS. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by pre-HPLC to give the desired products.

Compound ID/ Conditions Analytical Data 113/Condition 2 LCMS: 353[M + 1]112/Condition 2 LCMS: 353[M + 1] 114/Condition 2 LCMS: 371[M + 1]111/Condition 2 LCMS: 353[M + 1] ¹H NMR(CDCl₃, 400 MHz): δ 8.17 (d, 1H,J = 9.6 Hz), 7.56 (d, 2H, J = 7.2 Hz), 7.48 (t, 2H, J = 8.0 Hz)7.42-7.34 (m, 2H), 7.12 (s, 1H), 6.98 (t, 1H, J = 8.0 Hz), 4.82 (s, 2H),3.90 (t, 2H, J = 5.6 Hz), 2.98(t, 2H, J = 5.6 Hz).

Example 13: Preparation of Compounds 242-244

Step 1: Preparation of Compound 3

To a mixture of 2-phenoxyacetic acid (7.33 g, 48.16 mmol, 1.00 eq) inDCM (100.00 mL) was added oxalyl chloride (9.17 g, 72.24 mmol, 1.50 eq)dropwise at 0° C. under N₂, followed by catalytic amount DMF. Themixture was stirred at 0° C. for 2 hours. TLC showed the reaction wascompleted. The mixture was concentrated in vacuum. The residue wasdiluted in DCM (50.00 mL), added to ethyl 4-oxopiperidine-3-carboxylate(10.00 g, 48.16 mmol, 1.00 eq) and TEA (14.62 g, 144.48 mmol, 3.00 eq)in DCM (80.00 mL) at 0° C. under N₂. The mixture was stirred at 20° C.for 10 hours. TLC showed the reaction was completed. The mixture waspoured into water (100 mL) and stirred for 5 min. The aqueous phase wasextracted with DCM (50 mL*2). The combined organic phase was washed withsaturated brine (50 mL*2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography (Petroleum ether/Ethyl acetate=5/1) to afford ethyl4-oxo-1-(2-phenoxyacetyl)piperidine-3-carboxylate (14.20 g, 46.51 mmol,96.57% yield) as yellow solid. LCMS: 306 [M+1].

Step 2: Preparation of Compound 4

To a mixture of ethyl 4-oxo-1-(2-phenoxyacetyl)piperidine-3-carboxylate(12.00 g, 39.30 mmol, 1.00 eq) in EtOH (200.00 mL) was added N2H4-H2O(2.36 g, 47.16 mmol, 1.20 eq) in one portion under N₂. The mixture wasstirred at 80° C. for 3 hours. TLC showed the reaction was completed.The mixture was cooled and concentrated in vacuum to afford1-(3-hydroxy-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone(10.00 g, 36.59 mmol, 93.11% yield) as white solid. LCMS: 274 [M+I].

Step 3: Preparation of Compound 5

To a mixture of1-(3-hydroxy-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-phenoxy-ethanone(3.00 g, 10.98 mmol, 1.00 eq) in Py (30.00 mL) was added1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(5.10 g, 14.27 mmol, 1.30 eq) in one portion at 20° C. under N₂. Themixture was stirred at 20° C. for 16 hours. TLC showed the reaction wascompleted. The mixture was concentrated in vacuum. The residue waspoured into water (15 mL) and stirred for 2 min. The aqueous phase wasextracted with ethyl acetate (15 mL*2). The combined organic phase waswashed with saturated brine (10 mL*2), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by silicagel chromatography (Petroleum ether/Ethyl acetate=1/1) to afford[5-(2-phenoxyacetyl)-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridin-3-yl]trifluoromethanesulfonate (4.10 g, 10.11 mmol, 92.12% yield) as yellowsolid. LCMS: 406 [M+1].

Preparation of Compound 242

To a mixture of[5-(2-phenoxyacetyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate(200.00 mg, 493.40 umol, 1.00 eq) and (2-fluorophenyl)boronic acid(138.07 mg, 986.80 umol, 2.00 eq) in dioxane (5.00 mL) was addedPd(dppf)Cl2 (36.10 mg, 49.34 umol, 0.10 eq), DPPF (13.68 mg, 24.67 umol,0.05 eq), K3PO4 (314.20 mg, 1.48 mmol, 3.00 eq) in one portion under N₂.The mixture was stirred at 110° C. for 10 hours. LCMS showed thereaction was completed. The mixture was poured into water (10 mL) andstirred for 2 min. The aqueous phase was extracted with ethyl acetate(10 mL*2). The combined organic phase was washed with saturated brine(10 mL*2), dried over anhydrous Na₂SO₄, filtered and concentrated invacuum. The residue was purified by pre-HPLC(FA) to afford1-[3-(2-fluorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]-2-phenoxy-ethanone(35.46 mg, 100.11 umol, 20.29% yield, 99.2% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.51-7.61 (m, 1H), 7.39-7.49 (m, 1H),7.18-7.33 (m, 4H), 6.83-7.02 (m, 3H), 4.90 (s, 1H), 4.80-4.82 (m, 1H),4.64-4.70 (m, 2H), 3.87-4.00 (m, 2H), 2.78-2.97 (m, 2H). LCMS: 352[M+1].

Preparation of Compound 243

To a mixture of[5-(2-phenoxyacetyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate(200.00 mg, 493.40 umol, 1.00 eq) and (3-fluorophenyl)boronic acid(138.07 mg, 986.80 umol, 2.00 eq) in dioxane (5.00 mL) was addedPd(dppf)Cl2 (36.10 mg, 49.34 umol, 0.10 eq), DPPF (13.68 mg, 24.67 umol,0.05 eq), K3PO4 (314.20 mg, 1.48 mmol, 3.00 eq) in one portion under N₂.The mixture was stirred at 110° C. for 10 hours. LCMS showed thereaction was completed. The mixture was poured into water (10 mL) andstirred for 2 min. The aqueous phase was extracted with ethyl acetate(10 mL*2). The combined organic phase was washed with saturated brine(10 mL*2), dried over anhydrous Na₂SO₄, filtered and concentrated invacuum. The residue was purified by pre-HPLC(FA) to afford1-[3-(3-fluorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]-2-phenoxy-ethanone(45.32 mg, 126.61 umol, 25.66% yield, 98.16% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.33-7.53 (m, 3H), 7.19-7.32 (m, 2H),7.05-7.15 (m, 1H), 6.99 (d, J=7.91 Hz, 3H), 4.92 (br. s., 2H), 4.80-4.85(m, 2H), 3.86-3.99 (m, 2H), 2.88-2.96 (m, 1H), 2.77-2.84 (m, 1H). LCMS:352 [M+1].

Preparation of Compound 244

To a mixture of[5-(2-phenoxyacetyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate(100.00 mg, 246.70 umol, 1.00 eq) and (4-fluorophenyl)boronic acid(69.04 mg, 493.40 umol, 2.00 eq) in dioxane (5.00 mL) was addedPd(dppf)Cl2 (18.05 mg, 24.67 umol, 0.10 eq), DPPF (13.68 mg, 24.67 umol,0.10 eq) and K3PO4 (157.10 mg, 740.10 umol, 3.00 eq) in one portionunder N₂. The mixture was stirred at 110° C. for 12 hours. LCMS showedthe reaction was completed. The mixture was poured into water (10 mL)and stirred for 1 min. The aqueous phase was extracted with ethylacetate (10 mL*2). The combined organic phase was washed with saturatedbrine (10 mL*2), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by pre-HPLC(FA) to afford1-[3-(4-fluorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]-2-phenoxy-ethanone(8.00 mg, 20.80 umol, 8.43% yield, 91.35% purity) as yellow solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.62 (br. s., 2H), 7.14-7.34 (m, 4H),6.87-7.03 (m, 3H), 5.00-5.12 (m, 2H), 4.80 (br. s., 2H), 3.90 (br. s.,2H), 2.75-2.95 (m, 2H). LCMS: 352 [M+1].

Example 14: Preparation of Compounds 142, 143, 144, 145, 147, 148, 150,163, 164, and 165

General Procedure

To a mixture of phenol (0.35 mmol, 1.2 eq) in MeCN (5 mL) was addedK₂CO₃ (60 mg, 0.435 mmol, 1.5 eq) and NaI (2.17 mg, 14.51 umol, 0.05 eq)at 25° C., followed by compound 1 (80 mg, 0.29 mmol, 1 eq). The mixturewas heated to 80° C. and stirred for 18 hours. TLC showed the reactionwas completed. The mixture was cooled to 25° C. The mixture added into10 mL water. The aqueous phase was extracted with DCM (10 mL*2). Thecombined organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by pre-TLC to give thedesired product.

Comp. ID Analytical Data 142 LCMS(M + 1): 352 143 LCMS(M + 1): 352 144LCMS(M + 1): 352 145 LCMS(M + 1): 348 147 LCMS(M + 1): 348 148 LCMS(M +1): 368 150 LCMS(M + 1): 368 1H NMR (400 MHz, DMSO-d6) d 12.66-13.16 (m,1H), 7.21-7.76 (m, 7H), 6.87-7.09 (m, 2H), 4.94-5.05 (m, 2H), 4.71 (br.s., 2H), 3.77 (d, J = 15.18 Hz, 2H), 2.85 (br. s., 1H), 2.68 (d, J =1.63 Hz, 1H) 163 LCMS(M + 1): 402 164 LCMS(M + 1): 402 165 LCMS(M + 1):402

Example 15: Preparation of Compound 169

General Procedure

To a mixture of Compound 1 (80 mg, 0.40 mml, 1 eq) and carboxylic acid(0.48 mmol, 1.2 eq) in DCM (5.00 mL) was added DIPEA (62.27 mg, 0.48mmol, 1.2 eq) and HATU (305.3 mg, 0.80 mmol, 2 eq) at 25° C. The mixturewas stirred at 25° C. for 5 h. TLC showed the reaction was completed.The mixture was added into 10 mL water. The aqueous phase was extractedwith DCM (10 mL*2). The combined organic phase was dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bypre-TLC to give the desired product.

Compound ID Analytical Data

LCMS (M + 1): 382

Example 16: Preparation of Compound 276

Step 1: Preparation of Compound 5

To a mixture ofN-(3-chlorophenyl)-3-hydroxy-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(3.60 g, 12.30 mmol, 1.00 eq) in Py (30.00 mL) was added1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(6.15 g, 17.22 mmol, 1.40 eq) in one portion under N₂. The mixture wasstirred at 10° C. for 16 hours. TLC showed the reaction was completed.The mixture was concentrated in vacuum. The residue was diluted withethyl acetate (50 mL) and poured into 1N HCl (50 mL) and stirred for 3min. The aqueous phase was extracted with ethyl acetate (50 mL*2). Thecombined organic phase was washed with saturated brine (30 mL*2), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by silica gel chromatography (Petroleum ether/Ethylacetate=4/1, 1/1) to afford[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate (3.20 g, 7.19 mmol, 58.49% yield, 95.5%purity) as white solid. LCMS: 425 [M+1].

Step 2: Preparation of Compound 276

To a mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate (100.00 mg, 235.42 umol, 1.00 eq) and(2-fluorophenyl)boronic acid (65.88 mg, 470.84 umol, 2.00 eq) in dioxane(5.00 mL) was added Pd(dppf)Cl₂ (17.23 mg, 23.54 umol, 0.10 eq), DPPF(13.05 mg, 23.54 umol, 0.10 eq) and K₃PO₄ (149.92 mg, 706.26 umol, 3.00eq) in one portion under N₂. The reaction vessel was sealed and heatedin microwave at 120° C. for 2 hr. LCMS showed the reaction wascompleted. The mixture was poured into water (10 mL) and stirred for 3min. The aqueous phase was extracted with ethyl acetate (10 mL*2). Thecombined organic phase was washed with saturated brine (10 mL*2), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by prep-HPLC(FA) to affordN-(3-chlorophenyl)-3-(2-fluorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(13.56 mg, 35.69 umol, 15.16% yield, 97.59% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.54-7.62 (m, 1H), 7.50 (s, 1H), 7.40-7.48(m, 1H), 7.18-7.34 (m, 4H), 6.96-7.03 (m, 1H), 4.58-4.66 (m, 2H),3.83-3.92 (m, 2H), 2.86-2.95 (m, 2H). LCMS: 371 [M+1].

Example 17: Preparation of Compound 277

To a mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate (100.00 mg, 235.42 umol, 1.00 eq) and(3-fluorophenyl)boronic acid (65.88 mg, 470.84 umol, 2.00 eq) in dioxane(5.00 mL) was added Pd(dppf)Cl₂ (17.23 mg, 23.54 umol, 0.10 eq), DPPF(13.05 mg, 23.54 umol, 0.10 eq) and K₃PO₄ (149.92 mg, 706.26 umol, 3.00eq) in one portion under N₂. The mixture was stirred at 110° C. for 12hours. LCMS showed the reaction was completed. The mixture was pouredinto water (10 mL) and stirred for 2 min. The aqueous phase wasextracted with ethyl acetate (10 mL*2). The combined organic phase waswashed with saturated brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byprep-HPLC(FA) to affordN-(3-chlorophenyl)-3-(3-fluorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(15.36 mg, 40.97 umol, 17.40% yield, 98.9% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.38-7.56 (m, 1H), 7.26-7.33 (m, 1H),7.19-7.26 (m, 1H), 7.06-7.15 (m, 1H), 6.97-7.03 (m, 1H), 4.76-4.81 (m,2H), 3.84-3.92 (m, 2H), 2.84-2.92 (m, 2H). LCMS: 371 [M+1].

Example 18: Preparation of Compound 278

To a mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate (100.00 mg, 235.42 umol, 1.00 eq) and(4-fluorophenyl)boronic acid (65.88 mg, 470.84 umol, 2.00 eq) in dioxane(5.00 mL) was added Pd(dppf)Cl₂ (17.23 mg, 23.54 umol, 0.10 eq), DPPF(13.05 mg, 23.54 umol, 0.10 eq) and K₃PO₄ (149.92 mg, 706.26 umol, 3.00eq) in one portion under N₂. The mixture was stirred at 110° C. for 12hours. LCMS showed the reaction was completed. The mixture was pouredinto water (10 mL) and stirred for 2 min. The aqueous phase wasextracted with ethyl acetate (10 mL*2). The combined organic phase waswashed with saturated brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byprep-HPLC(FA) to affordN-(3-chlorophenyl)-3-(4-fluorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(35.42 mg, 92.53 umol, 39.30% yield, 96.87% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) D 7.62-7.73 (m, 1H), 7.50-7.56 (m, 1H),7.26-7.32 (m, 1H), 7.16-7.26 (m, 3H), 6.97-7.03 (m, 1H), 4.73-4.78 (m,2H), 3.83-3.91 (m, 2H), 2.83-2.91 (m, 2H). LCMS: 371 [M+1].

Example 19: Preparation of Compound 279

To a mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate (120.00 mg, 282.50 umol, 1.00 eq) ando-tolylboronic acid (76.82 mg, 565.00 umol, 2.00 eq) in dioxane (5.00mL) was added Pd(dppf)Cl₂ (20.67 mg, 28.25 umol, 0.10 eq), DPPF (15.66mg, 28.25 umol, 0.10 eq) and K₃PO₄ (179.90 mg, 847.50 umol, 3.00 eq) inone portion under N₂. The mixture was sealed and heated in microwave at130° C. for 2 hr. LCMS showed the reaction was completed. The mixturewas poured into water (10 mL) and stirred for 3 min. The aqueous phasewas extracted with ethyl acetate (10 mL*2). The combined organic phasewas washed with saturated brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byprep-HPLC(FA) to affordN-(3-chlorophenyl)-3-(o-tolyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(25.25 mg, 68.18 umol, 24.14% yield, 99.06% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.47-7.52 (m, 1H), 7.16-7.36 (m, 6H),6.94-7.03 (m, 1H), 4.46 (s, 2H), 3.82-3.94 (m, 2H), 2.84-2.95 (m, 2H),2.29 (s, 3H). LCMS: 367 [M+1].

Example 20: Preparation of Compound 280

To a mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate (120.00 mg, 282.50 umol, 1.00 eq) andm-tolylboronic acid (76.82 mg, 565.00 umol, 2.00 eq) in dioxane (5.00mL) was added Pd(dppf)Cl₂ (20.67 mg, 28.25 umol, 0.10 eq), DPPF (15.66mg, 28.25 umol, 0.10 eq) and K₃PO₄ (179.90 mg, 847.50 umol, 3.00 eq) inone portion under N₂. The reaction vessel was sealed and heated inmicrowave at 130° C. for 2 hr. LCMS showed the reaction was completed.The mixture was poured into water (10 mL) and stirred for 1 min. Theaqueous phase was extracted with ethyl acetate (10 mL*2). The combinedorganic phase was washed with brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bypre-HPLC(FA) to affordN-(3-chlorophenyl)-3-(m-tolyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(15.32 mg, 41.05 umol, 14.53% yield, 98.3% purity) as white solid. LCMS:367 [M+1].

Example 21: Preparation of Compound 281

To a mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate (120.00 mg, 282.50 umol, 1.00 eq) andp-tolylboronic acid (76.82 mg, 565.00 umol, 2.00 eq) in dioxane (5.00mL) was added Pd(dppf)Cl₂ (20.67 mg, 28.25 umol, 0.10 eq), DPPF (15.66mg, 28.25 umol, 0.10 eq) and K₃PO₄ (179.90 mg, 847.50 umol, 3.00 eq) inone portion under N₂. The reaction vessel was sealed and heated inmicrowave at 130° C. for 2 hr. LCMS showed the reaction was completed.The mixture was poured into water (10 mL) and stirred for 1 min. Theaqueous phase was extracted with ethyl acetate (10 mL*2). The combinedorganic phase was washed with brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byprep-HPLC(FA) to affordN-(3-chlorophenyl)-3-(p-tolyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(20.35 mg, 54.25 umol, 19.20% yield, 97.8% purity) as white solid. LCMS:367 [M+1].

Example 22: Preparation of Compound 291

To a mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate (100.00 mg, 235.42 umol, 1.00 eq) andpyrimidin-5-ylboronic acid (58.34 mg, 470.84 umol, 2.00 eq) in dioxane(5.00 mL) was added Pd(dppf)Cl₂ (17.23 mg, 23.54 umol, 0.10 eq), DPPF(13.05 mg, 23.54 umol, 0.10 eq) and K₃PO₄ (149.92 mg, 706.26 umol, 3.00eq) in one portion under N₂. The reaction vessel was sealed and heatedin microwave at 145° C. for 2 hr. LCMS showed showed the reaction wascompleted. The mixture was poured into water (10 mL) and stirred for 2min. The aqueous phase was extracted with ethyl acetate (10 mL*2). Thecombined organic phase was washed with saturated brine (10 mL*2), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by prep-HPLC(FA) to affordN-(3-chlorophenyl)-3-pyrimidin-5-yl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(25.63 mg, 69.47 umol, 29.51% yield, 96.16% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) D 9.12 (d, J=5.02 Hz, 1H), 7.48-7.58 (m, 1H),7.29 (s, 1H), 7.19-7.26 (m, 1H), 6.98-7.05 (m, 1H), 4.83 (s, 2H),3.85-3.93 (m, 2H), 2.86-2.95 (m, 2H). LCMS: 355 [M+1].

Example 23: Preparation of Compound 325

To a mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate (120.00 mg, 282.50 umol, 1.00 eq) and(4-methoxyphenyl)boronic acid (64.39 mg, 423.75 umol, 1.50 eq) indioxane (5.00 mL) was added Pd(dppf)Cl₂ (20.67 mg, 28.25 umol, 0.10 eq),DPPF (15.66 mg, 28.25 umol, 0.10 eq) and K₃PO₄ (179.90 mg, 847.50 umol,3.00 eq) in one portion under N₂. The reaction vessel was sealed andheated in microwave at 145° C. for 3 hr. LCMS showed the reaction wascompleted. The mixture was poured into water (10 mL) and stirred for 2min. The aqueous phase was extracted with ethyl acetate (10 mL*2). Thecombined organic phase was washed with brine (10 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by prep-HPLC(FA) to affordN-(3-chlorophenyl)-3-(4-methoxyphenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(34.26 mg, 83.85 umol, 31.68% yield, 93.7% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) D 7.55 (s, 3H), 7.19-7.32 (m, 2H), 7.03 (d,J=8.78 Hz, 3H), 4.73-4.77 (m, 2H), 3.85-3.89 (m, 2H), 3.84 (s, 3H),2.83-2.89 (m, 2H). LCMS: 383 [M+1].

Example 24: Preparation of Compound 326

A mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]trifluoromethanesulfonate (120.00 mg, 282.50 umol, 1.00 eq),(3-methoxyphenyl)boronic acid (85.86 mg, 565.00 umol, 2.00 eq),Pd(dppf)Cl₂ (20.67 mg, 28.25 umol, 0.10 eq), DPPF (15.66 mg, 28.25 umol,0.10 eq) and K₃PO₄ (179.90 mg, 847.50 umol, 3.00 eq) were taken up intoa microwave tube in dioxane (5.00 mL). The sealed tube was heated at145° C. for 3 hr under microwave. LCMS showed the reaction wascompleted. The mixture was filtered and concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC (FA)to giveN-(3-chlorophenyl)-3-(3-methoxyphenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (20.62 mg, 53.75 umol, 19.03% yield, 99.8%purity) as light yellow solid. ¹H NMR (400 MHz, METHANOL-d₄) ppm 7.52(s, 1H), 7.39 (t, J=7.84 Hz, 1H), 7.28 (s, 1H), 7.17-7.26 (m, 3H), 7.00(d, J=7.91 Hz, 1H), 6.92-6.97 (m, 1H), 4.77 (s, 2H), 3.83-3.92 (m, 5H),2.88 (t, J=5.65 Hz, 2H). LCMS: 383 [M+1].

Example 25: Preparation of Compound 327

A mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]trifluoromethanesulfonate(120.00 mg, 282.50 umol, 1.00 eq), (2-methoxyphenyl)boronic acid (85.86mg, 565.00 umol, 2.00 eq), Pd(dppf)Cl₂ (20.67 mg, 28.25 umol, 0.10 eq),DPPF (15.66 mg, 28.25 umol, 0.10 eq) and K₃PO₄ (179.90 mg, 847.51 umol,3.00 eq) were taken up into a microwave tube in dioxane (5.00 mL). Thesealed tube was heated at 145° C. for 3 hr under microwave. LCMS showedthe starting material was consumed, the desired product was appeared.The mixture was filtered and concentrated under reduced pressure to givea residue. The residue was purified by prep-HPLC (FA) to giveN-(3-chlorophenyl)-3-(2-methoxyphenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(4.62 mg, 11.98 umol, 4.24% yield, 99.3% purity) as a light yellowsolid. ¹H NMR (400 MHz, METHANOL-d₄) ppm 7.50 (s, 1H), 7.37-7.44 (m,2H), 7.25-7.30 (m, 1H), 7.18-7.24 (m, 1H), 7.12 (d, J=8.03 Hz, 1H), 7.05(t, J=7.59 Hz, 1H), 6.99 (d, J=7.40 Hz, 1H), 4.60 (s, 2H), 3.82-3.96 (m,5H), 2.88 (t, J=5.58 Hz, 2H). LCMS: 383 [M+1].

Example 26: Preparation of Compound 286

A mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-yl]trifluoromethanesulfonate(120.00 mg, 282.50 umol, 1.00 eq), 3-pyridylboronic acid (69.45 mg,565.00 umol, 2.00 eq), Pd(dppf)Cl₂ (20.67 mg, 28.25 umol, 0.10 eq), DPPF(15.66 mg, 28.25 umol, 0.10 eq) and K₃PO₄ (179.90 mg, 847.50 umol, 3.00eq) were taken up into a microwave tube in dioxane (5.00 mL). The sealedtube was heated at 145° C. for 3 hr under microwave. LCMS showed thestarting material/desired product=1/1. The mixture was filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by pre-HPLC (FA) to giveN-(3-chlorophenyl)-3-(3-pyridyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (13.00 mg, 34.02 umol, 12.04% yield, 92.6%purity) as a white solid.

¹H NMR (400 MHz, METHANOL-d₄) ppm 8.87 (d, J=1.51 Hz, 1H), 8.50-8.55 (m,1H), 8.12 (td, J=1.77, 8.00 Hz, 1H), 7.51-7.57 (m, 2H), 7.27-7.32 (m,1H), 7.20-7.26 (m, 1H), 6.98-7.03 (m, 1H), 4.81 (s, 2H), 3.89 (t, J=5.77Hz, 2H), 2.90 (t, J=5.71 Hz, 2H). LCMS: 354 [M+1].

Example 27: Preparation of Compound 472

To a mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate (100.00 mg, 235.42 umol, 1.00 eq) and(2-fluoro-3-pyridyl)boronic acid (66.35 mg, 470.84 umol, 2.00 eq) indioxane (5.00 mL) was added Pd(dppf)Cl₂ (17.23 mg, 23.54 umol, 0.10 eq),DPPF (13.05 mg, 23.54 umol, 0.10 eq), KBr (2.80 mg, 23.54 umol, 0.10 eq)and K₃PO₄ (149.92 mg, 706.26 umol, 3.00 eq) in one portion under N₂. Thereaction vessel was sealed and heated in microwave at 145° C. for 2hour. LCMS showed the desired compound was detected. The mixture waspoured into water (10 mL) and stirred for 2 min. The aqueous phase wasextracted with ethyl acetate (10 mL*2). The combined organic phase waswashed with saturated brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byprep-HPLC(FA) to affordN-(3-chlorophenyl)-3-(2-fluoro-3-pyridyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(17.56 mg, 46.71 umol, 19.84% yield, 98.9% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 8.22-8.28 (m, 1H), 8.10-8.19 (m, 1H),7.48-7.52 (m, 1H), 7.40-7.46 (m, 1H), 7.18-7.30 (m, 2H), 6.96-7.02 (m,1H), 4.62-4.69 (m, 2H), 3.85-3.93 (m, 2H), 2.86-2.94 (m, 2H). LCMS: 372[M+1].

Example 28: Preparation of Compound 473

To a mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate (100.00 mg, 235.42 umol, 1.00 eq) and(6-fluoro-3-pyridyl)boronic acid (66.35 mg, 470.84 umol, 2.00 eq) indioxane (5.00 mL) was added Pd(dppf)Cl₂ (17.23 mg, 23.54 umol, 0.10 eq),DPPF (13.05 mg, 23.54 umol, 0.10 eq) and K₃PO₄ (149.92 mg, 706.26 umol,3.00 eq) in one portion under N₂. The reaction vessel was sealed andheated in microwave at 145° C. for 2 hr. LCMS showed showed the reactionwas completed. The mixture was poured into water (10 mL) and stirred for2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). Thecombined organic phase was washed with saturated brine (10 mL*2), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by prep-HPLC(FA) to affordN-(3-chlorophenyl)-3-(6-fluoro-3-pyridyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(21.36 mg, 57.05 umol, 24.23% yield, 99.3% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) 8.46-8.54 (m, 1H), 8.18-8.28 (m, 1H),7.49-7.57 (m, 1H), 7.16-7.32 (m, 3H), 6.98-7.04 (m, 1H), 4.78 (s, 2H),3.88 (s, 2H), 2.84-2.95 (m, 2H). LCMS: 372 [M+1].

Example 29: Preparation of Compound 495

To a mixture of[5-[(3-chlorophenyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]trifluoromethanesulfonate (30.00 mg, 70.62 umol, 1.00 eq) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (22.04mg, 105.93 umol, 1.50 eq) in dioxane (2.00 mL) and H₂O (200.00 uL) wasadded K₃PO₄ (29.98 mg, 141.24 umol, 2.00 eq), XPHOS-PD-G₂ (5.56 mg, 7.06umol, 0.10 eq) in one portion under N₂. The mixture was stirred at 110°C. for 10 hour. LCMS showed the desired product was detected. Themixture was poured into water (10 mL) and stirred for 2 min. The aqueousphase was extracted with ethyl acetate (10 mL*2). The combined organicphase was washed with saturated brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byprep-HPLC(FA) to affordN-(3-chlorophenyl)-3-(1-methylpyrazol-4-yl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(5.20 mg, 14.25 umol, 20.18% yield, 97.8% purity) as white solid. ¹H NMR(400 MHz, METHANOL-d₄) 7.90-7.95 (m, 1H), 7.79-7.83 (m, 1H), 7.52-7.56(m, 1H), 7.29-7.34 (m, 1H), 7.20-7.28 (m, 1H), 6.99-7.05 (m, 1H),4.63-4.69 (m, 2H), 3.93-4.00 (m, 3H), 3.81-3.89 (m, 2H), 2.79-2.89 (m,2H). LCMS: 357 [M+1].

Example 30: Preparation of Compound 562

To a mixture of 3-bromo-N-(3-chlorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (80.00 mg, 224.96 umol, 1.00 eq) and3-thienylboronic acid (57.57 mg, 449.92 umol, 2.00 eq) in dioxane (2.00mL) and H₂O (200.00 uL) was added Pd(dppf)Cl₂ (16.46 mg, 22.50 umol,0.10 eq), Na₂CO₃ (47.69 mg, 449.92 umol, 2.00 eq) in one portion underN₂. The reaction vessel was sealed and heated in microwave at 110° C.for 2 hour. LCMS showed the starting material was consumed completely.The mixture was poured into water (10 mL) and stirred for 2 min. Theaqueous phase was extracted with ethyl acetate (10 mL*2). The combinedorganic phase was washed with brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byprep-HPLC(FA) to affordN-(3-chlorophenyl)-3-(3-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(16.00 mg, 44.05 umol, 19.58% yield, 98.8% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.61-7.66 (m, 1H), 7.51-7.57 (m, 2H),7.46-7.51 (m, 1H), 7.28-7.35 (m, 1H), 7.20-7.27 (m, 1H), 6.97-7.05 (m,1H), 4.72-4.78 (m, 2H), 3.83-3.92 (m, 2H), 2.82-2.90 (m, 2H). LCMS: 359[M+1].

Example 31: Preparation of Compounds 496, and 497

Step 1: Preparation of Compound 2

To a mixture of ethyl 3-aminopropanoate (50.00 g, 320.55 mmol, 1.00 eq,HCl salt) in MeOH (150.00 mL) was added NaOH (13 g, 320.55 mmol, 1.00eq). The mixture was heated to 70° C. Acrylonitrile (21.8 g, 410.1 mmol,1.26 eq) was added dropwise into the above mixture. And the mixture wasstirred at 70° C. for 4 h. It was cooled 25° C., Boc₂O (6.39 g, 29.30mmol, 0.90 eq) was added. Then the mixture was stirred at 25° C. for 16h. TLC showed the reaction completed. The mixture was filtered, thefiltrate was wahsed with water (500 mL), extracted with EtOAc (500mL*3), the filtrate was dried over Na₂SO₄ and concentrated to giveCompound 2A (6.70 g, 24.79 mmol, 76.15% yield), which was used directly.¹H NMR (400 MHz, CHLOROFORM-d) 6=3.71 (s, 3H), 3.50-3.63 (m, 4H),2.56-2.70 (m, 4H), 1.49 (s, 9H).

Step 2: Preparation of Compound 3

To a mixture of ethyl3-[tert-butoxycarbonyl(2-cyanoethyl)amino]propanoate (70.00 g, 258.95mmol, 1.00 eq) in PhMe (150.00 mL) was added NaH (10.46 g, 261.54 mmol,1.01 eq) in three portions. The mixture was stirred at 110° C. for 4 h.TLC showed the reaction completed. The reaction was quenched withaqueous saturate NH₄Cl (200 mL), the aqueous was acidified with HCl (2N)to pH=6, then the mixture was extracted with EtOAc (150 mL*3), theorganic layer was washed with brine (100 mL), dried over Na₂SO₄ andconcentrated to give Compound 3 which was used directly. ¹H NMR (400MHz, CHLOROFORM-d) 6=4.40 (br. s., 1H), 4.16-4.26 (m, 1H), 3.58 (brs.,2H), 3.41 (d, J=7.28 Hz, 1H), 2.67 (d, J=14.31 Hz, 1H), 2.53 (dd,J=5.77, 9.54 Hz, 1H), 1.52 (s, 9H).

Step 3: Preparation of Compound 4

To a mixture of tert-butyl 3-cyano-4-oxo-piperidine-1-carboxylate (20.00g, 89.18 mmol, 1.00 eq) in EtOH (200.00 mL) was added NH₂NH₂.H₂O (8.93g, 178.36 mmol, 2.00 eq) in one portion. The mixture was stirred at 80°C. for 2 h. TLC showed the reaction worked well. The mixture wasconcentrated to give Compound 4 (19.70 g, 82.67 mmol, 92.70% yield).

Step 4: Preparation of Compound 5

To a suspension of Compound 4 (40.00 g, 0.47 mol, 1.00 eq) and CuBr₂ (44g, 0.58 mol, 1.20 eq) in 500 mL of acetonitrile was added t-BuONO (20.2g, 0.58 mol, 1.20 eq) dropwise at 0° C. The contents were allowed tostir at 50° C. for 4 h. TLC showed the reaction completed. Then it wasquenched with HCl (IM, 300 mL), extracted with EtOAc (200 mL*3), theorganic layer was washed with brine (300 mL), dried over Na₂SO₄ andconcentrated to give Compound 5 (11.00 g, 36.40 mmol, 21.69% yield). ¹HNMR (400 MHz, CHLOROFORM-d) 6=4.33 (brs, 2H), 3.72 (brs, 2H), 2.83 (t,J=5.27 Hz, 2H), 1.50 (s, 9H).

Step 5: Preparation of Compound 6

To a mixture of Compound 5 (11.00 g, 36.40 mmol, 1.00 eq) in DCM (10.00mL) was added HCl/dioxane (4 M, 20.02 mL) in one portion at 0° C. Themixture was stirred at 0° C. for 1 h. The mixture was concentrated togive Compound 5 (HCl).

Preparation of Compound 260

To a mixture of 3-bromo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(10.50 g, 38.19 mmol, 1.00 eq, 2 HCl) in MeOH (350.00 mL) was addedK₂CO₃ (13.20 g, 95.48 mmol, 2.50 eq). Then the mixture was filtered, thefiltrate was used directly. And 1-chloro-3-isocyanato-benzene (5.86 g,38.19 mmol, 1.00 eq) was added slowly into above filtrate at 25° C. Thereaction was stirred at 25° C. for 1 h. LCMS showed the reaction workedwell. The mixture was concentrated. The residue was rinsed with a mixedsolution of PE/EA (10/1, 20 mL). The mixture was filtered and the cakewas collected to give Compound 260 (11.00 g, 30.93 mmol, 80.99% yield).¹H NMR (400 MHz, DMSO-d6) δ=12.95 (brs, 1H), 8.88 (s, 1H), 7.64 (s, 1H),7.41 (d, J=8.03 Hz, 1H), 7.26 (t, J=8.16 Hz, 1H), 6.99 (d, J=7.78 Hz,1H), 4.34 (s, 2H), 3.72 (brs, 2H), 2.72 (brs, 2H). LCMS: 355 [M+1].

Preparation of Compound 496

To a mixture Compound 260 (100.00 mg, 281.20 umol, 1.00 eq)1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (70.21mg, 337.44 umol, 1.20 eq) in dioxane (1.50 mL) was added Pd(dppf)Cl₂(20.58 mg, 28.12 umol, 0.10 eq) and Na₂CO₃ (65.57 mg, 618.64 umol, 2.20eq) in one portion. The mixture was stirred at 100° C. for 1 h viamicrowave. LCMS showed major was desired product. The mixture wasfiltered and the filtrate was concentrated. The residue was purified bypre-HPLC (FA) to give Compound 496 (22.00 mg, 59.19 umol, 21.05% yield).¹H NMR (400 MHz, METHANOL-d4) 6=7.47-7.56 (m, 2H), 7.26-7.33 (m, 1H),7.18-7.26 (m, 1H), 7.00 (d, J=7.53 Hz, 1H), 6.51 (d, J=1.76 Hz, 1H),4.60 (s, 2H), 4.04 (brs, 3H), 3.87 (t, J=5.65 Hz, 2H), 2.89 (t, J=5.65Hz, 2H). LCMS: 357 [M+1].

Preparation of Compound 497

To a mixture of Compound 260 (80.00 mg, 224.96 umol, 1.00 eq)1H-pyrazol-5-ylboronic acid (30.20 mg, 269.95 umol, 1.20 eq) in dioxane(1.50 mL) was added Pd(dppf)Cl₂ (16.46 mg, 22.50 umol, 0.10 eq), Na₂CO₃(65.57 mg, 618.64 umol, 2.20 eq) in one portion. The mixture was stirredat 100° C. for 1 h via microwave. LCMS showed DP:SM=1:1. The mixture wasfiltered and the filtrate was concentrated. The residue was purified bypre-HPLC (FA) to give Compound 497 (3.50 mg, 10.01 umol, 4.45% yield,98.00% purity)¹H NMR (400 MHz, METHANOL-d4) 6=7.71 (s, 1H), 7.55 (s,1H), 7.29-7.35 (m, 1H), 7.23 (t, J=8.03 Hz, 1H), 7.00 (d, J=7.78 Hz,1H), 6.66 (d, J=1.76 Hz, 1H), 4.77 (s, 2H), 3.87 (t, J=5.65 Hz, 2H),2.86 (t, J=5.52 Hz, 2H). LCMS: 343 [M+1].

Example 32: Preparation of Compound 555

Step 1: Preparation of Compound 2

A mixture of 3-bromo-1-methyl-pyrazole (100.00 mg, 621.12 umol, 1.00eq), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (236.59mg, 931.68 umol, 1.50 eq), AcOK (152.39 mg, 1.55 mmol, 2.50 eq) andPd(dppf)Cl₂ (22.72 mg, 31.06 umol, 0.05 eq) in dioxane (3.00 mL) washeated to 120° C. for 4 hrs. The mixture was filtered and the filtratewas used directly for the next step.

Step 2: Preparation of Compound 555

A mixture of Compound 3 (60.00 mg, 168.72 umol, 1.00 eq), Compound 2(70.21 mg, 337.44 umol, 2.00 eq), Na₂CO₃ (35.77 mg, 337.44 umol, 2.00eq) and Pd(dppf)Cl₂ (6.17 mg, 8.44 umol, 0.05 eq) in dioxane (2.00mL)/H₂O (400.00 uL) was heated to 110° C. in microwave for 1 hr. Thereaction mixture was diluted with brine (60 mL) and extracted with EA(80 mL). The organic layer was concentrated under reduced pressure togive a yellow residue. The residue was purified by prep-TLC to giveimpure product (20 mg). The impure product was purified by prep-HPLC(FA) to afford the desired product, Compound 555, (6.00 mg, 16.65 umol,9.87% yield, 99.00% purity) as white solid. LCMS: 357/359 [M+1]. ¹H NMR(400 MHz, METHANOL-d₄) 6=7.65 (s, 1H), 7.55 (t, J=1.94 Hz, 1H),7.30-7.38 (m, 1H), 7.18-7.29 (m, 1H), 6.92-7.08 (m, 1H), 6.62 (d, J=2.26Hz, 1H), 4.78 (s, 2H), 3.97 (s, 3H), 3.87 (t, J=5.71 Hz, 2H), 2.81-2.92(m, 2H).

Example 33: Preparation of Compound 287

Step 1: Preparation of Compound 2

To a mixture of Compound 1 (100.00 mg, 330.94 umol, 1.00 eq) in dioxane(2.00 mL) was added Pd(dppf)Cl₂ (24.21 mg, 33.09 umol, 0.10 eq) andNa₂CO₃ (70.15 mg, 661.88 umol, 2.00 eq) in one portion. The mixture wasstirred at 100° C. for 1 h via mircrowave. LCMS showed major was desireproduct. The mixture was filtered and concentrated. The residue waspurified with column chromatography on silica gel (PE:EA=1:1) to giveCompound 2 (70.00 mg, 233.06 umol, 70.42% yield). LCMS: 301[M+1].

Step 2: Preparation of Compound 3

To a mixture of Compound 2 (70.00 mg, 233.06 umol, 1.00 eq) in DCM (5.00mL) was added HCl/MeOH (4 M, 6.21 mL, 106.65 eq) in one portion. Themixture was stirred at 0° C. for 0.5 h. TLC showed the reactioncompleted. The mixture was concentrated to give Compound 3 (65.00 mg,crude).

Step 3: Preparation of Compound 287

To a mixture of Compound 3 (50.00 mg, crude) in DCM (5.00 mL) was addedTEA (64.83 mg, 640.64 umol, 3.50 eq) and 1-chloro-3-isocyanato-benzene(28.11 mg, 183.04 umol, 1.00 eq) in one portion. The mixture was stirredat 0° C. for 0.5 h. LCMS showed product was major. The mixture wasconcentrated. The residue was purified by pre-HPLC (FA) to give Compound287 (32.00 mg, 88.64 umol, 48.43% yield, 98% purity). ¹H NMR (400 MHz,METHANOL-d4) δ=8.59 (d, J=5.52 Hz, 2H), 7.72 (d, J=5.27 Hz, 2H), 7.53(s, 1H), 7.27-7.34 (m, 1H), 7.19-7.26 (m, 1H), 7.01 (d, J=8.03 Hz, 1H),4.84 (s, 2H), 3.88 (t, J=5.65 Hz, 2H), 2.89 (t, J=5.52 Hz, 2H). LCMS:354[M+1].

Example 34: Preparation of Compound 436

Step 1: Preparation of Compound 2

To a solution of 3-methylcyclohexanone (2.00 g, 17.83 mmol, 1.00 eq) inEtOH (15.00 mL) and H₂O (15.00 mL) was added NaOAc (4.39 g, 53.49 mmol,3.00 eq) and NH₂OH.HCl (6.20 g, 89.15 mmol, 5.00 eq) in sequence, thenthe mixture was stirred at 20° C. for 16 hr. TLC indicated the reactionwas completed and one new spot formed. The mixture was concentrated toremove the EtOH and then added into water (30 mL), extracted with EA (30mL*3), the organic layers were dried over Na₂SO₄, filtered andconcentrated to give the Compound 2 (2.00 g, 15.73 mmol, 88.20% yield).

Step 2: Preparation of Compound 3

To a solution of 3-methylcyclohexanone oxime (1.00 g, 7.86 mmol, 1.00eq) in MeOH (10.00 mL) was added Raney-Ni (67.34 mg, 786.00 umol, 0.10eq) under argon, and then stirred at 30° C. for 16 hr under H₂ (45 Psi).TLC indicated the reaction was completed and one new spot formed. Themixture was filtered by diatomite, then the filtrate was added intoHCl/MeOH (4M, 30 mL), the mixture was stirred at 10° C. for 5 min, andconcentrated to give the Compound 3 (800.00 mg, 5.35 mmol, 68.01% yield,HCl) as white solid.

Step 3: Preparation of Compound 436

To a mixture of 3-methylcyclohexanamine (63.49 mg, 424.25 umol, 1.00 eq,HCl) and TEA (429.30 mg, 4.24 mmol, 10.00 eq) in DCM (20.00 mL) wasadded triphosgene (50.36 mg, 169.70 umol, 0.40 eq) at 0° C. and stirred10 min, 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (100.00mg, 424.25 umol, 1.00 eq, HCl) was added into the reaction and stirredat 0° C. for 2 hr. LC-MS showed the reaction was completed and one mainpeak with desired MS was detected. The reaction mixture was quenched byaddition water 20 mL at 10° C., extracted with DCM (20 mL*3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-TLC to obtained Compound 436 (40.00 mg, 118.19 umol, 27.86% yield)as light yellow solid.

LCMS: 339[M+H]. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 7.30-7.77 (m, 5H)4.65 (d, J=4.27 Hz, 2H) 3.88-3.97 (m, 1H) 3.72-3.82 (m, 2H) 3.55-3.65(m, 1H) 2.75-2.87 (m, 2H) 1.62-1.96 (m, 4H) 1.13-1.61 (m, 5H) 0.92-1.00(m, 3H).

Example 35: Preparation of Compound 559

To a solution of 3-amino-2-fluoro-benzonitrile (57.75 mg, 424.25 umol,1.00 eq) in DCM (3 mL) was added TEA (100 mg) and TRIPHOSGENE (50.36 mg,169.70 umol, 0.40 eq) at 0° C. under N₂, the mixture stirred at thistemperature for 10 min, then added into the solution of3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c]pyridine (100.00 mg,424.25 umol, 1.00 eq, HCl) which was freed by TEA (71 mg) in DCM (3 mL),stirred at 10° C. for 2 hr. LC-MS showed the reaction was completed andone main peak with desired MS was detected. The mixture was added intoHCl (0.5 M, 10 mL), extracted with DCM (20 mL*3). The organic layerswere concentrated. The residue was purified by prep-HPLC (FA condition)to give Compound 559 (45.00 mg, 119.55 umol, 28.18% yield, 96% purity)as white solid. LCMS: 262 [M+H]. 1H NMR (400 MHz, METHANOL-d4) δ ppm7.72-7.80 (m, 1H) 7.57-7.70 (m, 2H) 7.43-7.53 (m, 3H) 7.33-7.40 (m, 1H)7.29 (s, 1H) 4.81 (s, 2H) 3.91 (t, J=5.77 Hz, 2H) 2.90 (t, J=5.65 Hz,2H).

Example 36: Preparation of Compound 560

To a solution of 5-amino-2-fluoro-benzonitrile (57.75 mg, 424.25 umol,1.00 eq) in DCM (3.00 mL) was added TRIPHOSGENE (125.90 mg, 424.25 umol,1.00 eq) and TEA (42.93 mg, 424.25 umol, 1.00 eq) at 0° C., the mixturewas stirred 10 min, then3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (100.00 mg,424.25 umol, 1.00 eq, HCl) was added into it, the reaction mixture wasstirred at 10° C. for 2 hr. LC-MS showed the reaction was completed andone main peak with desired MS was detected. The mixture was concentratedand diluted with 10 mL HCl (0.5 M), then extracted with EA (20 mL*3),the organic layers were dried over Na₂SO₄, then filtered andconcentrated. The residue was purified by prep-HPLC (FA condition) togive Compound 560 (50.00 mg, 135.60 umol, 31.96% yield, 98% purity) aswhite solid. LCMS: 362 [M+H]. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 7.80(dd, J=5.52, 2.76 Hz, 1H) 7.57-7.72 (m, 3H) 7.47 (t, J=7.40 Hz, 2H) 7.38(d, J=7.28 Hz, 1H) 7.26 (t, J=9.03 Hz, 1H) 4.79 (s, 2H) 3.88 (t, J=5.77Hz, 2H) 2.88 (t, J=5.65 Hz, 2H).

Example 37: Preparation of Compound 556

Step 1: Preparation of Compound 3

To a solution of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(500.00 mg, 2.12 mmol, 1.00 eq, HCl) in DCM (5.00 mL) was added TEA(1.07 g, 10.61 mmol, 5.00 eq), the mixture was stirred for 10 min, and3-bromoaniline (2.12 mmol, 1.00 eq, HCl) was added into the reactionmixture and stirred at 10° C. for 16 hr. TLC indicated the reaction wascompleted and one new main spot formed. The mixture was added into HCl(0.5 M, 20 mL) and extracted with DCM (30 mL*3). The organic layers wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby column chromatography to give the Compound 3 (450.00 mg, 1.04 mmol,49.16% yield, 92% purity) as white solid.

Step 2: Preparation of Compound 556

A mixture ofN-(3-bromophenyl)-3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(130.00 mg, 327.23 umol, 1.00 eq), cyclopropylboronic acid (140.55 mg,1.64 mmol, 5.00 eq), K₂CO₃ (135.68 mg, 981.69 umol, 3.00 eq), Pd₂(dba)₃(26.97 mg, 29.45 umol, 0.09 eq) anddicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl] phosphane (12.48 mg,26.18 umol, 0.08 eq) in dioxane (2.00 mL) was stirred at 110° C. for 16hour under N₂ atmosphere. LC-MS showed the reaction was completed andone main peak with desired MS was detected. The mixture was added intothe water (10 mL) and extracted with DCM (20 mL*3). The organic layerswere dried over Na₂SO₄, filtered and concentrated. The residue waspurified by prep-TLC to give desired compound as a light yellow solid,which was further purified by prep-HPLC (FA condition) to affordCompound 556 (20.00 mg, 55.24 umol, 16.88% yield, 99% purity) as whitesolid. LCMS: 359 [M+H]. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 7.60-7.67(m, 1H) 7.43-7.51 (m, 1H) 7.33-7.40 (m, 1H) 7.05-7.16 (m, 3H) 6.74-6.80(m, 1H) 4.77 (s, 2H) 3.84-3.91 (m, 2H) 2.84-2.91 (m, 2H) 1.80-1.91 (m,1H) 0.88-0.96 (m, 2H) 0.63-0.70 (m, 2H).

Example 38: Preparation of Compounds 317 and 318

Step 1: Preparation of Compounds 2A and 2B

To a solution of LiHMDS (1 M, 15.47 mL, 2.20 eq) in THF (10.00 mL) wasadded tert-butyl-2-methyl-4-oxo-piperidine-1-carboxylate (1.50 g, 7.03mmol, 1.00 eq) dropwise at −70° C. and stirred for 0.5 hr, then PhCOCl(988.68 mg, 7.03 mmol, 1.00 eq) in THF (2.00 mL) was added dropwise at−70° C. The reaction was stirred at −70° C. to 16° C. for 3 hr. Thereaction was quenched with sat.NH₄Cl (20 mL) and then extracted with EA(20 mL*2). The combined organic phase was washed with brine (15 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by flash silica gel chromatography (˜5% Ethylacetate/Petroleum ether gradient) to give a mixture of 2A and 2B (1.75g) as yellow oil. LCMS: 218[M+1].

Step 2: Preparation of Compounds 3A and 3B

To a solution of 2A and 2B (1.75 g mixture of 2A and 2B, 5.51 mmol, 1.00eq) in EtOH (15.00 mL) was added N₂H4.H₂O (324.51 mg, 5.51 mmol, 1.00eq), the solution was stirred at 90° C. for 3 hr. The solution wasconcentrated to give a mixture of 3A and 3B (1.75 g, 4.47 mmol, 81.08%yield, 80% purity) as light yellow solid. LCMS: 314[M+1].

Step 3: Preparation of Compounds 4A and 4B

To a mixture of 3A and 3B (330.00 mg, 842.40 umol, 1.00 eq) in dioxane(3.00 mL) was added HCl/dioxane (4 M, 10.00 mL, 47.48 eq). The mixturewas stirred at 15° C. for 1 hr. Solid was formed, and the solvent wasevaporated to afford a mixture of 4A and 4B (210.00 mg, crude, HCl salt)as light yellow solid.

Step 4: Preparation of Compound 317 and 318

A mixture of 6-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine and4-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (210.00mg, 840.87 umol, 1.00 eq, HCl) in DCM (10.00 mL) was added TEA (170.18mg, 1.68 mmol, 2.00 eq) and 1-chloro-3-isocyanato-benzene (129.13 mg,840.87 umol, 1.00 eq). The mixture was stirred at 15° C. for 1 hr. LCMSshowed the material was consumed completely, and a major peak withdesired product detected. The mixture was washed with water (10 mL), theaqueous layer was extracted with DCM (15 mL*3). The combined organiclayer was dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was purified by prep-HPLC (FA) to afford a mixture ofN-(3-chlorophenyl)-4-methyl-3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamideandN-(3-chlorophenyl)-6-methyl-3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(160.00 mg, 1:1 from H NMR, 436.16 umol, 51.87% yield, 4 isomersdetected by SFC) as white solid. The mixture was separated by SFC(Instrument: SFC 80, Column: OD-10 um. Mobile phase: A for CO₂ and B forMeOH (0.1% NH₃H₂O), Gradient: B 35%, Flow rate: 65 mL/min, Backpressure: 100 bar, Column temperature: 35° C., Wavelength: 220 nm) togive Compound 318, Enantiomer 1 (peak 1, Rt=3.003 min, 22.76 mg, purity:98.6%), Compound 317, Enantiomer 1 (peak 2, Rt=3.219 min, 26.27 mg,purity: 99.9%), Compound 318, Enantiomer 2 (peak 3, Rt=3.509 min, 24.3mg, purity: 99.1%) and Compound 317, Enantiomer 2 (peak 4, Rt=3.930 min,27.21 mg, purity: 99.0%), all as white solid.

Compound 318, Enantiomer 1: ¹H NMR (400 MHz, METHANOL-d4) δ ppm 7.68 (d,J=7.53 Hz, 2H), 7.56 (d, J=1.76 Hz, 1H), 7.50 (t, J=7.65 Hz, 2H), 7.42(d, J=7.28 Hz, 1H), 7.32-7.38 (m, 1H), 7.27 (t, J=8.03 Hz, 1H), 7.05 (d,J=7.78 Hz, 1H), 5.77 (q, J=6.27 Hz, 1H), 4.40 (dd, J=13.80, 4.52 Hz,1H), 3.37 (brs, 1H), 2.75-2.95 (m, 2H), 1.31 (d, J=6.53 Hz, 3H). LCMS:367/369 [M+1].

Compound 317, Enantiomer 1: ¹H NMR (400 MHz, METHANOL-d4) δ ppm 7.69 (d,J=7.53 Hz, 2H), 7.46-7.59 (m, 3H), 7.39 (s, 1H), 7.29-7.34 (m, 1H),7.22-7.28 (m, 1H), 7.03 (d, J=7.78 Hz, 1H), 5.07 (d, J=15.31 Hz, 1H),4.99 (s, 1H), 4.48 (d, J=15.31 Hz, 1H), 3.09 (dd, J=15.81, 5.77 Hz, 1H),2.73 (d, J=15.81 Hz, 1H), 1.28 (d, J=6.78 Hz, 3H). LCMS: 367/369 [M+1].LCMS: 367/369 [M+1].

Compound 318, Enantiomer 2: ¹H NMR (400 MHz, METHANOL-d4) δ ppm 7.68 (d,J=7.53 Hz, 2H), 7.57 (s, 1H), 7.50 (t, J=7.65 Hz, 2H), 7.33-7.44 (m,2H), 7.24-7.30 (m, 1H), 7.05 (d, J=7.53 Hz, 1H), 5.72-5.83 (m, 1H),4.35-4.47 (m, 1H), 3.37 (brs, 1H), 2.76-2.94 (m, 2H), 1.31 (d, J=6.53Hz, 3H). LCMS: 367/369 [M+1].

Compound 317, Enantiomer 2: ¹H NMR (400 MHz, METHANOL-d4) δ ppm 7.69 (d,J=7.78 Hz, 2H), 7.47-7.58 (m, 3H), 7.37-7.44 (m, 1H), 7.30-7.34 (m, 1H),7.21-7.28 (m, 1H), 7.04 (s, 1H), 5.08 (d, J=15.31 Hz, 1H), 4.99-5.01 (m,1H), 4.48 (d, J=15.31 Hz, 1H), 3.10 (dd, J=15.81, 5.77 Hz, 1H), 2.73 (d,J=15.81 Hz, 1H), 1.28 (d, J=6.78 Hz, 3H). LCMS: 367/369 [M+1].

Example 39: Preparation of Compounds 542 and 583

Step 1: Preparation of Compound 2

To a mixture of 2-(1H-imidazol-4-yl)ethanamine (1.00 g, 5.43 mmol, 1.00eq, 2 HCl) in H2O (8.00 mL) was added HCHO (244.59 mg, 8.15 mmol, 1.50eq) in one portion under N₂. The mixture was stirred at 100° C. for 10hours. LCMS showed the reaction was completed. The mixture wasconcentrated in cacuum to afford4,5,6,7-tetrahydro-3H-imadazo[4,5-c]pyridine (1.25 g, crude, 2 HCl) asyellow solid.

Step 2: Preparation of Compound 3

To a mixture of 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (669.00 mg,3.41 mmol, 1.00 eq, 2 HCl) in dioxane (5.00 mL) and H₂O (3.00 mL) wasadded Na₂CO₃ (904.06 mg, 8.53 mmol, 2.50 eq) and Boc₂O (819.11 mg, 3.75mmol, 1.10 eq) in one portion at 15° C. under N₂. The mixture wasstirred at 15° C. for 10 hours. LCMS showed the reaction was completed.The residue was extracted with ethyl acetate (40 mL*2). The combinedorganic phase was washed with brine (40 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bysilica gel chromatography (Ethyl acetate) to afford tert-butyl3,4,6,7-tetrahydroimidazo[4,5-c] pyridine-5-carboxylate (740.00 mg, 2.85mmol, 83.58% yield, 86% purity) as yellow solid. ¹H NMR (400 MHz,CHLOROFORM-D) 9.08-9.41 (M, 1 h), 7351 (S, 1H), 4.48 (s, 2H), 3.63-3.83(m, 2H), 2.59-2.76 (m, 2H), 1.47 (s, 9H). LCMS: 224 [M+1].

Step 3: Preparation of Compounds 4A and 4B

To a mixture of tert-butyl3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (300.00 mg, 1.34mmol, 1.00 eq) and iodobenzene (356.36 mg, 1.75 mmol, 1.30 eq) indioxane (3.00 mL) was added K₃PO₄ (570.44 mg, 2.69 mmol, 2.00 eq), Cul(51.18 mg, 268.73 umol, 0.20 eq) and N,N′-dimethylethane-1,2-diamine(236.89 mg, 2.69 mmol, 2.00 eq) in one portion under N₂. The mixture wasstirred at 110° C. for 16 hours. LCMS showed the reaction was completed.The mixture was poured into water (20 mL) and stirred for 2 min. Theaqueous phase was extracted with ethyl acetate (20 mL*2). The combinedorganic phase was washed with brine (20 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bysilica gel chromatography (Petroleum ether/Ethyl acetate=4/1) to affordtert-butyl 3-phenyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5-carboxylate(32.00 mg, 106.89 umol, 7.98% yield) as yellow oil and tert-butyl1-phenyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5-carboxylate (46.00 mg,153.66 umol, 11.47% yield) as yellow oil.

Compound 4A: ¹H NMR (400 MHz, METHANOL-d₄) 7.80 (s, 1H), 7.57 (s, 2H),7.48-7.52 (m, 1H), 7.44 (d, J=1.25 Hz, 2H), 4.47 (s, 2H), 3.74-3.80 (m,2H), 2.66-2.74 (m, 2H), 1.39-1.49 (m, 9H). LCMS: 300 [M+1].

Compound 4B: ¹H NMR (400 MHz, METHANOL-d₄) 7.82 (s, 1H), 7.55 (s, 2H),7.43 (s, 3H), 4.44-4.53 (m, 2H), 3.69-3.77 (m, 2H), 2.62-2.73 (m, 2H),1.50 (s, 9H). LCMS: 300 [M+1].

Step 4a: Preparation of Compound 5A

To a mixture of tert-butyl3-phenyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5-carboxylate (30.00 mg,100.21 umol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (4 M,4.00 mL, 159.66 eq) in one portion under N₂. The mixture was stirred at15° C. for 1 hour. TLC (Ethyl acetate:Petroleum ether=1:1) showed thereaction was completed. The mixture was concentrated in vacuum to afford3-phenyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (23.62 mg, 100.21umol, 100.00% yield, HCl) as yellow solid.

Step 5a: Preparation of Compound 542

To a mixture of 3-phenyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (23.62mg, 100.21 umol, 1.00 eq, HCl) and TEA (30.42 mg, 300.62 umol, 3.00 eq)in DCM (4.00 mL) was added 1-chloro-3-isocyanato-benzene (15.39 mg,100.21 umol, 1.00 eq) in one portion at 15° C. under N₂. The mixture wasstirred at 15° C. for 1 hours. LCMS showed the reaction was completed.The mixture was poured into water (10 mL) and stirred for 2 min. Theaqueous phase was extracted with DCM (10 mL*2). The combined organicphase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byprep-HPLC(FA) to affordN-(3-chlorophenyl)-3-phenyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5-carboxamide (17.00 mg, 47.36 umol, 47.26% yield, 98.3%purity) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.82-7.91 (m,1H), 7.55-7.62 (m, 3H), 7.49 (d, J=1.63 Hz, 6H), 7.18-7.29 (m, 3H),6.96-7.03 (m, 1H), 4.61 (s, 2H), 3.89 (s, 2H), 2.81 (br. s., 2H). LCMS:353 [M+1].

Step 4b: Preparation of Compound 5B

To a mixture of tert-butyl1-phenyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5-carboxylate (36.00 mg,120.25 umol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (4 M,2.00 mL, 66.53 eq) in one portion under N₂. The mixture was stirred at15° C. for 30 min. TLC (Ethyl acetate:Petroleum ether=2:1) showed thereaction was completed. The mixture was concentrated in vacuum to afford1-phenyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (28.34 mg, 120.23umol, 100.00% yield, HCl) as yellow solid.

Step 5b: Preparation of Compound 583

To a mixture of 1-phenyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (28.34mg, 120.23 umol, 1.00 eq, HCl) and TEA (36.50 mg, 360.69 umol, 3.00 eq)in DCM (2.00 mL) was added 1-chloro-3-isocyanato-benzene (18.46 mg,120.23 umol, 1.00 eq) in one portion at 15° C. under N₂. The mixture wasstirred at 15° C. for 30 min. LCMS showed the reaction was completed.The mixture was poured into water (10 mL) and stirred for 2 min. Theaqueous phase was extracted with DCM (10 mL*2). The combined organicphase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byprep-HPLC (FA) to affordN-(3-chlorophenyl)-1-phenyl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5-carboxamide (24.00 mg, 64.35 umol, 53.52% yield, 94.6%purity) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) 8.34-8.38 (m, 1H),7.60 (d, J=7.65 Hz, 1H), 7.48-7.57 (m, 4H), 7.25 (s, 1H), 7.00-7.05 (m,1H), 4.68 (s, 2H), 3.87 (t, J=5.52 Hz, 2H), 2.80 (t, J=5.21 Hz, 2H).LCMS: 353 [M+1].

Example 40: Preparation of Compound 576

Step 1: Preparation of Compound 2

A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (60.00 g, 301.13mmol, 1.00 eq) in toluene (600.00 mL) was added t-BuOK (50.68 g, 451.70mmol, 1.50 eq) at 0° C. under N₂. The mixture was stirred at 0° C. for30 min. Then ethyl formate (33.46 g, 451.70 mmol, 1.50 eq) was added at0° C., and the mixture was stirred at 15° C. for 16 hr under N₂atmosphere. TLC showed the reaction was completed. The mixture waspoured into ice-water (600 mL), extracted with EA (300 mL*2), thecombined organic layer was washed with 10% NaOH (300 mL), the combinedaqueous layer was adjust pH to 4 by 1N HCl, then the aqueous layer wasextracted with EA (600*3), the combined organic layer was dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum to give tert-butyl(3E)-3-(hydroxymethylene)-4-oxo-piperidine-1-carboxylate (70.60 g,crude) as a yellow oil and used directly in the next step.

Step 2: Preparation of Compound 3

A mixture of tert-butyl(3E)-3-(hydroxymethylene)-4-oxo-piperidine-1-carboxylate (70.00 g,308.02 mmol, 1.00 eq), NH₂NH₂.H₂O (36.28 g, 616.04 mmol, 2.00 eq) inEtOH (700.00 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 90° C. for 5 hour under N₂ atmosphere. LCMSshowed the reaction was completed. The mixture was poured into HCl (0.5N, 700 mL) and stirred at 5 min. The aqueous phase was extracted withethyl acetate (300 mL*3). The combined organic phase was washed withbrine (700 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum to give tert-butyl1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (65.00 g, 291.13mmol, 94.52% yield) as a yellow oil, which was used directly for nextstep. LCMS: 224 [M+1].

Step 3: Preparation of Compound 4

To a mixture of NaH (16.12 g, 403.10 mmol, 60% purity, 1.50 eq) in THF(750 mL) was added a solution of tert-butyl1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (60.00 g, 268.73mmol, 1.00 eq) in THF (50 mL) dropwise at 0° C. under N₂. The mixturewas stirred at 0° C. for 30 min. Then SEM-Cl (58.24 g, 349.35 mmol,61.96 mL, 1.30 eq) was added to the mixture dropwise at 0° C. under N₂.The mixture was stirred at 15° C. for 2.5 hr under N₂ atmosphere. TLCshowed the reaction was completed. The mixture was poured into ice-water(800 mL) and stirred at 5 min. The aqueous phase was extracted withethyl acetate (500 mL*3). The combined organic phase was washed withbrine (800 mL*2), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=100/1 to 20/1) to give tert-butyl1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (72.00 g, 203.66 mmol, 75.79% yield) as a white oil.¹H NMR (400 MHz, CHLOROFORM-d) ppm 7.32 (s, 1H), 5.32-5.41 (m, 2H),4.40-4.53 (m, 2H), 3.67-3.78 (m, 2H), 3.52-3.65 (m, 2H), 2.72-2.81 (m,2H), 1.48 (s, 9H), 0.87-0.92 (m, 2H), −0.02 (d, J=5.52 Hz, 9H).

Step 4: Preparation of Compound 5

A mixture of tert-butyl1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (20.00 g, 56.57 mmol, 1.00 eq) and HMPA(25.34 g, 141.42 mmol, 24.84 mL, 2.50 eq) in THF (200.00 mL) at −78° C.,then n-BuLi (2.5 M, 33.94 mL, 1.50 eq) was added in one portion at −78°C. under N₂. The mixture was stirred at −78° C. for 0.5 hr under N₂.Then 1,2-dibromo-1,1,2,2-tetrachloro-ethane (36.84 g, 113.14 mmol, 13.59mL, 2.00 eq) was added in one portion at −78° C. under N₂. The mixturewas stirred at 15° C. for 2.5 hr under N₂ atmosphere. TLC showed thereaction was completed. The mixture was poured into ice-water (300 mL)and stirred at 5 min. The aqueous phase was extracted with ethyl acetate(100 mL*3). The combined organic phase was washed with brine (300 mL*2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=100/1 to 30/1) to give tert-butyl3-bromo-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (8.30 g, 19.19 mmol, 33.93% yield) as ayellow oil. ¹H NMR (300 MHz, CHLOROFORM-d) ppm 5.40-5.42 (m, 1H), 5.38(s, 1H), 4.27-4.42 (m, 2H), 3.55-3.71 (m, 4H), 2.66-2.78 (m, 2H), 1.47(s, 9H), 0.91 (s, 2H), −0.03 (s, 9H).

Step 5: Preparation of Compound 7

To a mixture of tert-butyl3-bromo-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(100.00 mg, 231.25 umol, 1.00 eq) and 1H-pyrazole (23.62 mg, 346.88umol, 1.50 eq) in DMF (2.00 mL) was added Bu₄NCuI₂ (25.89 mg, 46.25umol, 0.20 eq), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (6.58 mg,46.25 umol, 0.20 eq) and t-BuOK (77.85 mg, 693.75 umol, 3.00 eq) in oneportion under N₂. The mixture was stirred at 100° C. for 16 hours. TLC(Petroleum ether:Ethyl acetate=3:1) showed the desired product wasdetected. The mixture was poured into water (10 mL) and stirred for 2min. The aqueous phase was extracted with ethyl acetate (15 mL*2). Thecombined organic phase was washed with brine (10 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum to affordtert-butyl3-pyrazol-1-yl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(60.00 mg, crude) as yellow oil. LCMS: 420 [M+1].

Step 6: Preparation of Compound 8

To a mixture of tert-butyl3-pyrazol-1-yl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(20.00 mg, 47.67 umol, 1.00 eq) in dioxane (1.00 mL) was addedHCl/dioxane (4 M, 4.00 mL, 335.64 eq). The mixture was stirred at 20° C.for 2 hours. TLC (Petroleum ether:Ethyl acetate=3:1) showed the reactionwas completed. The mixture was concentrated in vacuum to afford3-pyrazol-1-yl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (10.76 mg,47.68 umol, 100.00% yield, HCl) as yellow solid.

Preparation of Compound 576

To a mixture of3-(1-bicyclo[3.1.0]hexanyl)-4,5,6,7-tetrahydro-H-pyrazolo[4,3-c]pyridine (15.80 mg, 65.90 umol, 1.00 eq, HCl) and TEA (20.01 mg, 197.70umol, 3.00 eq) in DCM (2.00 mL) was added 1-chloro-3-isocyanato-benzene(9.11 mg, 59.31 umol, 0.90 eq) in one portion at 15° C. under N₂. Themixture was stirred at 15° C. for 30 min. LCMS showed the reaction wascompleted. The mixture was poured into water (10 mL) and stirred for 2min. The aqueous phase was extracted with DCM (10 mL*2). The combinedorganic phase was washed with brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byprep-HPLC (FA) to afford3-(1-bicyclo[3.1.0]hexanyl)-N-(3-chlorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (10.00 mg, 26.90 umol, 40.82% yield, 96.0%purity) as white solid. ¹H NMR (400 MHz, METHANOL-d4) ppm 8.08-8.18 (m,1H), 7.70-7.75 (m, 1H), 7.50-7.56 (m, 1H), 7.18-7.34 (m, 2H), 6.96-7.04(m, 1H), 6.44-6.52 (m, 1H), 4.77 (s, 2H), 3.86 (t, J=5.71 Hz, 2H), 2.86(t, J=5.65 Hz, 2H). LCMS: 343/345[M+1].

Example 41: Preparation of Compound 751

Step 1: Preparation of Compound 3

A mixture of[5-tert-butoxycarbonyl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]boronicacid (120.00 mg, 302.00 umol, 1.00 eq), 5-bromoisothiazole (59.44 mg,362.40 umol, 1.20 eq), XPhos (14.40 mg, 30.20 umol, 0.10 eq), Pd₂(dba)₃(13.83 mg, 15.10 umol, 0.05 eq) and Na₂CO₃ (80.02 mg, 755.00 umol, 2.50eq) in dioxane (4.00 mL) and H₂O (500.00 uL) was degassed and purgedwith N₂ for 3 times, and then the mixture was stirred at 105° C. for 1hour under N₂ atmosphere. LCMS showed the reaction was completed. Themixture was poured into water (10 mL) and stirred at 5 min. The aqueousphase was extracted with ethyl acetate (5 mL*3). The combined organicphase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byPrep-TLC (PE/EA=5/1) to give tert-butyl3-isothiazol-5-yl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (29.00 mg, 46.49 umol, 15.39% yield, 70%purity) as a white solid. LCMS: 437[M+1].

Step 2: Preparation of Compound 4

A mixture oftert-butyl3-isothiazol-5-yl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(29.00 mg, 66.42 umol, 1.00 eq) in HCl/dioxane (4 M, 5.00 mL, 301.11eq), and then the mixture was stirred at 15° C. for 0.5 hour. TLC showedthe reaction was completed. The mixture was concentrated in vacuum togive 5-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl) isothiazole(14.00 mg, 57.68 umol, 86.84% yield, HCl) as a white solid, which wasused directly for next step.

Preparation of Compound 751

A mixture of5-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)isothiazole (14.00mg, 57.68 umol, 1.00 eq, HCl), phenyl N-(3-chlorophenyl)carbamate (12.86mg, 51.91 umol, 0.90 eq), TEA (8.75 mg, 86.52 umol, 11.99 uL, 1.50 eq)in DCM (3.00 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 15° C. for 16 hour under N₂ atmosphere. LCMSshowed the reaction was completed. The mixture was poured into water (10mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5mL*3). The combined organic phase was washed with brine (10 mL*2), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by Prep-HPLC (FA) to giveN-(3-chlorophenyl)-3-isothiazol-5-yl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(11.10 mg, 30.85 umol, 53.48% yield) as a white solid. ¹H NMR (400 MHz,METHANOL-d4) ppm 8.50-8.54 (m, 1H), 7.51-7.57 (m, 2H), 7.30 (dd, J=1.00,2.01 Hz, 1H), 7.21-7.27 (m, 1H), 7.03 (s, 1H), 4.74 (s, 2H), 3.87 (t,J=5.71 Hz, 2H), 2.89 (t, J=5.71 Hz, 2H). LCMS: 360/362[M+1].

Example 42: Preparation of Compound 569

Step 1: Preparation of Compound 3

A solution oftert-butyl3-bromo-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(200.00 mg, 462.50 umol, 1.00 eq) and tributyl(thiazol-2-yl)stannane(259.58 mg, 693.75 umol, 1.50 eq) in THF (10.00 mL) was addedXPHOS-PD-G2 (36.39 mg, 46.25 umol, 0.10 eq). The mixture was stirred at80° C. for 16 hr under N₂ protection. TLC (Peteoleum ether/ethylacetate=5:1) showed material remained, and a new spot detected. Thesolvent was evaporated. The residue was purified by prep-TLC (Peteoleumether/ethyl acetate=5:1) to afford a crude product. The crude productre-purified by prep-HPLC (FA) to afford tert-butyl3-thiazol-2-yl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (40.00 mg, 43.97 umol, 9.51% yield, 48%purity) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.90-8.00 (m, 1H),7.48 (d, J=3.01 Hz, 1H), 5.95 (s, 1H), 4.70 (brs, 2H), 3.77 (brs, 2H),3.63-3.68 (m, 2H), 2.83 (d, J=5.27 Hz, 2H), 1.51 (s, 9H), 0.93 (d,J=8.28 Hz, 2H), −0.05 (s, 9H). LCMS: 437 [M+1].

Step 2: Preparation of Compound 4

A mixture oftert-butyl-3-thiazol-2-yl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(40.00 mg, 91.61 umol, 1.00 eq) and HCl/dioxane (4 M, 5.00 mL, 218.32eq) was stirred at 25° C. for 2 hr. The solvent was evaporated to afford2-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiazole (22.00 mg,90.64 umol, 98.94% yield, HCl) as white solid, which was not purifiedand used directly in the next step.

Preparation of Compound 569

To a mixture of2-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiazole (22.00 mg,90.64 umol, 1.00 eq, HCl) and phenyl N-(3-chlorophenyl)carbamate (22.45mg, 90.64 umol, 1.00 eq) in DCM (3.00 mL) was added TEA (18.34 mg,181.28 umol, 25.12 uL, 2.00 eq). The mixture was stirred at 25° C. for16 hr. LCMS showed the material was consumed completely, and majordesired MS detected. The solvent was evaporated. The residue waspurified by prep-HPLC (FA) to affordN-(3-chlorophenyl)-3-thiazol-2-yl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (14.41 mg, 40.05 umol, 44.18% yield, 100% purity)as white solid. ¹H NMR (400 MHz, MeOD) δ 7.90 (d, J=2.51 Hz, 1H),7.52-7.60 (m, 2H), 7.31-7.36 (m, 1H), 7.21-7.29 (m, 1H), 7.02 (d, J=8.03Hz, 1H), 4.89-4.97 (m, 2H), 3.89 (t, J=5.65 Hz, 2H), 2.91 (t, J=5.65 Hz,2H). LCMS: 360/362 [M+1].

Example 43: Preparation of Compound 726

Step 1: Preparation of Compound 2

A mixture of tert-butyl1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (5.70 g, 16.12 mmol, 1.00 eq) in THF(60.00 mL) at −78° C. under N₂. N-BuLi (2.5 M, 7.74 mL, 1.20 eq) wasadded in one portion at −78° C. under N₂. The mixture was stirred at−78° C. for 30 min. Then B(OMe)₃ (5.03 g, 48.36 mmol, 5.47 mL, 3.00 eq)was added in one portion at −78° C. under N₂. The mixture was stirred at15° C. for 1.5 hr under N₂ atmosphere. LCMS showed the startingmaterial/desired product=1/3. The mixture was poured into ice-NH₄Cl (aq.80 mL) and stirred at 5 min. The aqueous phase was extracted with ethylacetate (50 mL*3). The combined organic phase was washed with brine (80mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuumto give[5-tert-butoxycarbonyl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]boronicacid (6.80 g, crude) was obtained as a yellow solid, which was useddirectly for next step. LCMS: 398[M+1].

Step 2: Preparation of Compound 4

[5-tert-butoxycarbonyl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]boronicacid (120.00 mg, 302.00 umol, 1.00 eq), 4-bromo-2-methyl-thiazole (64.53mg, 362.40 umol, 1.20 eq), Pd₂(dba)₃ (13.83 mg, 15.10 umol, 0.05 eq),XPhos (14.40 mg, 30.20 umol, 0.10 eq) and Na₂CO₃ (80.02 mg, 755.00 umol,2.50 eq) were taken up into a microwave tube in dioxane (4.00 mL) andH₂O (500.00 uL) was degassed and purged with N₂ for 3 times. The sealedtube was heated at 105° C. for 1 hr under microwave. LCMS showed thereaction was completed. The mixture was poured into water (10 mL) andstirred at 5 min. The aqueous phase was extracted with ethyl acetate (5mL*3). The combined organic phase was washed with brine (10 mL*2), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by Prep-TLC (PE/EA=5/1) to givetert-butyl3-(2-methylthiazol-4-yl)-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(34.00 mg, 75.44 umol, 24.98% yield) as a light yellow solid. LCMS:451[M+1].

Step 3: Preparation of Compound 5

A mixture oftert-butyl3-(2-methylthiazol-4-yl)-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (34.00 mg,75.44 umol, 1.00 eq) in HCl/dioxane (4 M, 2.00 mL, 106.04 eq), and thenthe mixture was stirred at 20° C. for 15 min. TLC showed the reactionwas completed. The mixture was concentrated in vacuum to give2-methyl-4-(4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c]pyridin-3-yl)thiazole(15.00 mg, 58.42 umol, 77.44% yield, HCl) as a white solid, which wasused directly for next step.

Preparation of Compound 726

A mixture of 2-methyl-4-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiazole (15.00 mg, 58.42 umol, 1.00 eq, HCl),phenyl N-(3-chlorophenyl)carbamate (13.02 mg, 52.58 umol, 0.90 eq), TEA(8.87 mg, 87.63 umol, 12.15 uL, 1.50 eq) in DCM (3.00 mL) was degassedand purged with N₂ for 3 times, and then the mixture was stirred at 20°C. for 16 hour under N₂ atmosphere. LCMS showed the reaction wascompleted. The mixture was poured into water (10 mL) and stirred at 5min. The aqueous phase was extracted with DCM (5 mL*3). The combinedorganic phase was washed with brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byprep-HPLC (FA) to giveN-(3-chlorophenyl)-3-(2-methylthiazol-4-yl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(12.00 mg, 31.84 umol, 54.50% yield, 99.2% purity) as a white solid. ¹HNMR (400 MHz, METHANOL-d₄) ppm 7.54 (s, 1H), 7.28-7.33 (m, 1H),7.20-7.26 (m, 1H), 6.98-7.03 (m, 1H), 4.80 (s, 2H), 3.83-3.88 (m, 2H),2.84-2.89 (m, 2H), 2.76 (s, 3H). LCMS: 374/376[M+1].

Example 44: Preparation of Compound 730

Step 1: Preparation of Compound 2

To a solution of 4-bromothiazole-2-carbaldehyde (500.00 mg, 2.60 mmol,1.00 eq) in DCM (10.00 mL) was added DAST (838.19 mg, 5.20 mmol, 687.04uL, 2.00 eq) at −78° C. dropwise under N₂ protection. The mixture wasstirred at 25° C. for 16 hr. TLC (Petroleum ether/ethyl acetate=10:1)showed material was consumed completely, and a new spot detected. Themixture was poured into water (10 mL), extracted with ethyl acetate (10mL*2), the combined organic layer was dried over anhydrous Na₂SO₄,concentrated. The residue was purified by chromatography (silica gel,eluting with Petroleum ether/ethyl acetate=100:1) to afford4-bromo-2-(difluoromethyl)thiazole (300.00 mg, 1.40 mmol, 53.91% yield)as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (s, 1H), 6.75 (t,J=52.00 Hz, 1H).

Step 2: Preparation of Compound 4

To a solution of 4-bromo-2-(difluoromethyl)thiazole (300.00 mg, 1.40mmol, 1.00 eq) and[5-tert-butoxycarbonyl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-H-pyrazolo[4,3-c]pyridin-3-yl]boronicacid (556.29 mg, 1.40 mmol, 1.00 eq) in dioxane (10.00 mL) were addedPd₂(dba)₃ (64.10 mg, 70.00 umol, 0.05 eq), XPhos (66.74 mg, 140.00 umol,0.10 eq) and Na₂CO₃ (296.77 mg, 2.80 mmol, 2.00 eq). The mixture wasstirred at 100° C. for 16 hr under N₂ protection. LCMS showed materialwas consumed completely, and desired MS detected. TLC (Petroleumether/ethyl acetate=10:1) showed a major product. The solvent wasevaporated. The residue was purified by chromatography (silica gel,eluting with Petroleum ether/ethyl acetate=10:1) to affordtert-butyl3-[2-(difluoromethyl)thiazol-4-yl]-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo [4,3-c]pyridine-5-carboxylate(196.00 mg, 237.62 umol, 16.97% yield, 59% purity) as light yellow oil.¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.34 (s, 1H), 6.74-7.06 (m, 1H),5.62 (s, 1H), 5.38 (s, 1H), 4.70 (brs, 1H), 4.45 (brs, 1H), 3.66-3.78(m, 3H), 3.52-3.61 (m, 1H), 2.80 (d, J=17.07 Hz, 2H), 1.45-1.56 (m, 9H),0.86-1.00 (m, 2H), −0.04-0.06 (m, 9H). LCMS: 487 [M+1].

Step 3: Preparation of Compound 5

A mixture of tert-butyl3-[2-(difluoromethyl)thiazol-4-yl]-1-(2-trimethylsilyl ethoxymethyl)-6,7-dihydro-4H-pyrazolo [4,3-c]pyridine-5-carboxylate (190.00mg, 390.42 umol, 1.00 eq) and HCl/dioxane (4 M, 5.00 mL, 51.23 eq) wasstirred at 25° C. for 1 hr. The solvent was evaporated to afford2-(difluoromethyl)-4-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)thiazole(114.00 mg, 389.42 umol, 99.74% yield, HCl) as white solid, which wasnot purified and used directly in the next step.

Preparation of Compound 730

To a solution of2-(difluoromethyl)-4-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-yl)thiazole(114.00 mg, 389.42 umol, 1.00 eq, HCl) in DCM (4.00 mL) were added TEA(78.81 mg, 778.84 umol, 107.96 uL, 2.00 eq) and phenylN-(3-chlorophenyl)carbamate (96.45 mg, 389.42 umol, 1.00 eq). Themixture was stirred at 25° C. for 16 hr. LCMS showed the material wasconsumed completely, and major desired MS detected. The solvent wasevaporated. The residue was purified by prep-HPLC (FA) to affordN-(3-chlorophenyl)-3-[2-(difluoromethyl)thiazol-4-yl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(29.83 mg, 72.09 umol, 18.51% yield, 99.04% purity) as white solid. ¹HNMR (400 MHz, MeOD) δ 7.94 (s, 1H), 7.49 (s, 1H), 7.26 (s, 1H),6.92-7.23 (m, 3H), 4.74-4.81 (m, 2H), 3.83 (t, J=5.65 Hz, 2H), 2.85 (t,J=5.52 Hz, 2H). LCMS: 410/412 [M+1].

Example 45: Preparation of Compound 645

Step 1: Preparation of Compound 2

A mixture of 2-bromothiophene (400.00 mg, 2.45 mmol, 1.00 eq),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(933.23 mg, 3.68 mmol, 1.50 eq), AcOK (601.11 mg, 6.13 mmol, 2.50 eq),XPhos (116.80 mg, 245.00 umol, 0.10 eq) and Pd₂(dba)₃ (112.18 mg, 122.50umol, 0.05 eq) in dioxane (10.00 mL) was heated to 110° C. under N₂ for16 hrs. The reaction mixture was diluted with brine (60 mL) andextracted with EA (80 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a brownresidue. The residue was purified by silica gel column (PE/EA=100/1) toafford the desire product (420.00 mg, crude).

Preparation of Compound 645

A mixture of Compound 3 (60.00 mg, 168.72 umol, 1.00 eq),4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane (120.00 mg, 571.16umol, 3.39 eq), Na₂CO₃ (44.71 mg, 421.80 umol, 2.50 eq), XPhos (8.04 mg,16.87 umol, 0.10 eq) and Pd₂(dba)₃ (7.72 mg, 8.44 umol, 0.05 eq) indioxane (2.50 mL)/H₂O (300.00 uL) was heated to 110° C. in microwave for1 hr. The reaction mixture was diluted with brine (40 mL) and extractedwith EA (40 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a brown residue. The residuewas purified by prep-HPLC (FA) to afford desire product (13.00 mg, 34.92umol, 20.70% yield, 96.4% purity) as white solid. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.54-7.56 (m, 1H), 7.34-7.36 (m, 1H), 7.30-7.32 (m, 2H),7.25-7.27 (m, 1H), 7.13-7.16 (m, 1H), 7.00-7.05 (m, 1H), 4.75 (s, 2H),3.86-3.89 (m, 2H), 2.86-2.89 (m, 2H). LCMS: 359/361[M+1].

Example 46: Preparation of Compound 568

Step 1: Preparation of Compound 2

A mixture of Compound 1 (120.00 mg, 181.20 umol, 1.00 eq),5-bromothiazole (35.66 mg, 217.44 umol, 1.20 eq), Na₂CO₃ (48.01 mg,453.00 umol, 2.50 eq), XPhos (8.64 mg, 18.12 umol, 0.10 eq) andPd₂(dba)₃ (8.30 mg, 9.06 umol, 0.05 eq) in dioxane (2.50 mL)/H₂O (500.00uL) was heated to 110° C. in microwave for 1 hr. The mixture was dilutedwith EA (50 mL) and washed with brine (40 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure togive yellow oil. The yellow oil was purified by prep-TLC (EA/PE=2/3) toafford desire product (24.00 mg, 46.72 umol, 25.78% yield, 85% purity)as colorless oil. LCMS: 437 [M+1].

Step 2: Preparation of Compound 3

A mixture of Compound 2 (24.00 mg, 54.97 umol, 1.00 eq) in HCl/dioxane(4 M, 3.84 mL, 279.43 eq) was stirred at 18° C. for 0.5 hr. The mixturewas concentrated under reduced pressure to give yellow residue to afforddesire product (14.00 mg, crude, HCl) as yellow solid, which was useddirectly for the next step.

Preparation of Compound 568

To a solution of5-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiazole (14.00 mg,57.68 umol, 1.00 eq, HCl) and TEA (23.35 mg, 230.71 umol, 4.00 eq) inDCM (5.00 mL)/MeOH (500.00 uL) was added 1-chloro-3-isocyanato-benzene(7.97 mg, 51.91 umol, 0.90 eq) under N₂, and the mixture was stirred at18° C. for 0.5 hr. The reaction mixture was diluted with DCM (30 mL) andwashed with brine (30 mL). The organic layer was concentrated underreduced pressure to give yellow solid. The yellow solid was purified byprep-HPLC (FA) to afford desire product (8.00 mg, 21.57 umol, 37.39%yield, 97% purity) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ 9.00(s, 1H), 8.12 (s, 1H), 7.55-7.56 (m, 1H), 7.23-7.34 (m, 2H), 7.02-7.04(m, 1H), 4.76 (s, 2H), 3.88-3.90 (m, 2H), 2.88-2.91 (m, 2H). LCMS:360/362 [M+1].

Example 47: Preparation of Compound 570

Step 1: Preparation of Compound 2

A mixture of Compound 1 (120.00 mg, 181.20 umol, 1.00 eq),4-bromothiazole (35.66 mg, 217.44 umol, 1.20 eq), Na₂CO₃ (38.41 mg,362.40 umol, 2.00 eq), XPhos (8.64 mg, 18.12 umol, 0.10 eq) andPd₂(dba)₃ (8.30 mg, 9.06 umol, 0.05 eq) in dioxane (2.50 mL)/H₂O (500.00uL) was heated to 110° C. in microwave for 1 hr. The mixture was dilutedwith EA (50 mL) and washed with brine (40 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure togive yellow oil. The yellow oil was purified by prep-TLC (EA/PE=2/3) toafford desire product (50.00 mg, 68.71 umol, 37.92% yield, 60% purity)as colorless oil. LCMS: 437[M+1].

Step 2: Preparation of Compound 3

A mixture of Compound 2 (50.00 mg, 114.51 umol, 1.00 eq) in HCl/dioxane(4 M, 6.67 mL, 232.86 eq) was stirred at 18° C. for 0.5 hr. The mixturewas concentrated under reduced pressure to give yellow residue to afforddesire product (28.00 mg, crude, HCl) as yellow solid, which was useddirectly for the next step.

Preparation of Compound 570

To a solution of4-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiazole (28.00 mg,115.35 umol, 1.00 eq, HCl) and TEA (46.69 mg, 461.42 umol, 4.00 eq) inDCM (5.00 mL) was added 1-chloro-3-isocyanato-benzene (15.94 mg, 103.82umol, 0.90 eq) under N₂, and the mixture was stirred at 18° C. for 0.5hr. The reaction mixture was diluted with DCM (30 mL) and washed withbrine (30 mL). The organic layer was concentrated under reduced pressureto give yellow residue. The residue was purified by prep-HPLC (FA) toafford desire product (13.00 mg, 35.41 umol, 30.69% yield, 98% purity)as white solid. ¹H NMR (400 MHz, METHANOL-d₄) 6=9.09 (s, 1H), 7.82 (s,1H), 7.55-7.56 (m, 1H), 7.32-7.33 (m, 1H), 7.23-7.27 (m, 1H), 7.03-7.04(m, 1H), 4.86 (s, 2H), 3.87-3.90 (m, 2H), 2.88-2.91 (m, 2H). LCMS:360/362[M+1].

Example 48: Preparation of Compound 729

Step 1: Preparation of Compound 2

A mixture of Compound 1 (1.20 g, 1.81 mmol, 1.00 eq),4-bromothiazole-2-carbaldehyde (347.57 mg, 1.81 mmol, 1.00 eq), Na₂CO₃(479.60 mg, 4.52 mmol, 2.50 eq), XPhos (86.29 mg, 181.00 umol, 0.10 eq)and Pd₂(dba)₃ (82.87 mg, 90.50 umol, 0.05 eq) in dioxane (15.00 mL)/H₂O(2.00 mL) was heated to 110° C. in microwave for 1 hr. The mixture wasfiltered, the filtrated was diluted with EA (80 mL) and washed withbrine (80 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give brown oil. The brown oil waspurified by silica gel column (PE/EA=15/1) to afford desire product(724.00 mg, 856.99 umol, 47.35% yield, 55% purity) as colorless oil.LCMS: 465 [M+1].

Step 2: Preparation of Compound 3

A mixture of Compound 2 (100.00 mg, 118.37 umol, 1.00 eq) in HCl/dioxane(4 M, 4.00 mL, 135.17 eq) was stirred at 25° C. for 0.5 hr. The mixturewas concentrated under reduced pressure to afford desire product (32.00mg, 65.01 umol, 54.92% yield, 55% purity, HCl) as yellow solid, whichwas used directly for the next step.

Step 3: Preparation of Compound 4

To a solution of Compound 3 (32.00 mg, 65.01 umol, 1.00 eq, HCl) and TEA(19.73 mg, 195.03 umol, 27.03 uL, 3.00 eq) in DCM (5.00 mL)/MeOH (500.00uL) was added 1-chloro-3-isocyanato-benzene (9.48 mg, 61.76 umol, 7.46uL, 0.95 eq) under N₂, and the mixture was stirred at 25° C. for 0.5 hr.The reaction mixture was diluted with DCM (40 mL) and washed with brine(40 mL). The organic layer was concentrated under reduced pressure togive yellow residue. The residue was purified by prep-TLC(DCM/MeOH=12/1) to afford desire product (31.00 mg, 31.97 umol, 49.18%yield, 40% purity) as white solid. LCMS: 388/390[M+1].

Preparation of Compound 729

To a solution of Compound 4 (31.00 mg, 43.96 umol, 1.00 eq) in MeOH(2.00 mL) was added NaBH₄ (3.33 mg, 87.92 umol, 2.00 eq) and the mixturewas stirred at 25° C. for 0.5 hr. The mixture was quenched with brine(30 mL) and extracted with EA (30 mL). The organic layer was dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure to give yellow residue. The residue was purified by prep-HPLC(FA) to afford desire product (10.00 mg, 25.14 umol, 57.19% yield, 98%purity) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.68 (s, 1H),7.54-7.56 (m, 1H), 7.27-7.33 (m, 1H), 7.22-7.25 (m, 1H), 7.01-7.03 (m,1H), 4.92 (s, 2H), 4.82 (s, 2H), 3.86-3.89 (m, 2H), 2.87-2.90 (m, 2H).LCMS: 390/392[M+1].

Example 49: Preparation of Compound 741

Step 1: Preparation of Compound 2

Oxazole-4-carboxylic acid (500.00 mg, 4.42 mmol, 1.00 eq) was added toSOCl₂ (10.00 mL), the reaction mixture was warmed to 70° C. and stirredat 70° C. for 2 hours. TLC indicated starting material was consumedcompletely. The solvent was evaporated. Compound oxazole-4-carbonylchloride (570.00 mg, crude) was obtained as yellow oil. The crudeproduct was used in the next step directly without purification.

Step 2: Preparation of Compound 4

Cooled the three-necked round bottom flask to −78° C., LiHMDS (1 M, 5.20mL, 1.20 eq) was added under N₂, then a solution of tert-butyl4-oxopiperidine-1-carboxylate (690.83 mg, 3.46 mmol, 0.80 eq) in THF(10.00 mL) was added dropwise. The reaction mixture was stirred at −78°C. for one hour under N₂. To the mixture was added a solution ofoxazole-4-carbonyl chloride (570.00 mg, 4.33 mmol, 1.00 eq) in THF(10.00 mL). After addition, the reaction mixture was warmed to 30° C.and stirred at 30° C. for another 2 hours. Several new peaks were shownon LCMS and only 15% of desired compound was detected. The reactionmixture was added to aqueous solution of NH₄Cl (30 mL) and extractedwith EA (40 mL*3). The combined organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuum to afford tert-butyl3-(oxazole-4-carbonyl)-4-oxo-piperidine-1-carboxylate (930.00 mg, crude)as yellow oil. The crude product was used in the next step directlywithout purification. LCMS: 295 [M+1].

Step 3: Preparation of Compound 5

To a solution of tert-butyl3-(oxazole-4-carbonyl)-4-oxo-piperidine-1-carboxylate (500.00 mg, 1.70mmol, 1.00 eq) in EtOH (10.00 mL) was added NH₂NH₂H₂O (120.14 mg, 2.04mmol, 116.64 uL, 85% purity, 1.20 eq). The reaction mixture was warmedto 60° C. and stirred at 60° C. for one hour. LCMS showed startingmaterial was consumed completely and one main peak with desired MS wasdetected. The mixture was extracted with EA (20 mL*3) and water (15 mL),the organic phase was dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography to afford tert-butyl3-oxazol-4-yl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(180.00 mg, 620.01 umol, 36.47% yield) as yellow oil. LCMS: 291 [M+1].

Step 4: Preparation of Compound 6

To a solution of tert-butyl 3-oxazol-4-yl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (150.00 mg, 516.67 umol, 1.00 eq) indioxane (1.00 mL) was added HCl/dioxane (4 M, 3.00 mL, 23.23 eq), thereaction mixture was stirred at 30° C. for 30 minutes. TLC showedstarting material was consumed completely. Evaporate the solution on awater bath under reduced pressure using a rotary evaporator to afford4-(4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c]pyridin-3-yl)oxazole (95.00 mg,419.13 umol, 81.12% yield, HCl) as yellow solid. The crude product wasused in the next step directly without purification.

Preparation of Compound 741

To a mixture of4-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)oxazole (40.00 mg,176.48 umol, 1.20 eq, HCl) in DCM (3.00 mL) was added TEA (44.64 mg,441.19 umol, 61.16 uL, 3.00 eq), followed by phenylN-(3-chlorophenyl)carbamate (36.42 mg, 147.06 umol, 1.00 eq), thereaction mixture was stirred at 30° C. for 16 hours. LCMS showedm-ClPhNHCO2Ph was consumed completely and one main peak with desired MSwas detected. The mixture was extracted with DCM (15 mL*3) and water (15mL), the organic phase was dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. Further purification by prep-HPLC (FA) to affordCompound 741 (39.00 mg, 112.77 umol, 76.68% yield, 99.4% purity) aswhite solid. ¹H NMR (400 MHz, METHANOL-d4) δ 8.26 (s, 1H), 8.21 (s, 1H),7.53-7.54 (t, J=2.01 Hz, 1H), 7.30-7.32 (m, 1H), 7.21-7.25 (m, 1H),7.00-7.01 (dd, J=7.91, 1.00 Hz, 1H), 4.75 (s, 2H), 3.84-3.87 (t, J=5.71Hz, 2H), 2.84-2.87 (t, J=5.71 Hz, 2H). LCMS: 344/346 [M+1].

Example 50: Preparation of Compound 707

Step 1: Preparation of Compound 3

A mixture of compound 1 (200.00 mg, 503.33 umol, 1.00 eq), compound 2(99.40 mg, 503.33 umol, 1.00 eq), Na₂CO₃ (133.37 mg, 1.26 mmol, 2.50eq), XPhos (23.99 mg, 50.33 umol, 0.10 eq) and Pd₂(dba)₃ (23.05 mg,25.17 umol, 0.05 eq) in dioxane(5.00 mL)/H₂O (500.00 uL) was heated to100° C. and stirred for 16 h. TLC (Petroleum ether:Ethyl acetate=5:1)indicated desire product (R_(f)=0.7) was detected. Water (15 mL) wasadded to the mixture and extracted with EA (3*20 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by prep-TLC(PE:EA 5:1) to afford compound 3 (45.00 mg, crude) as light yellowliquid.

Step 2: Preparation of Compound 4

A solution of compound compound 3 (45.00 mg, 95.72 umol, 1.00 eq) inHCl/dioxane (228.84 umol, 3.00 mL, 2.00 eq) was stirred at 30° C. for 20min. Then the reaction mixture was concentrated to remove the solvent.Then another batch of HCl/dioxane (228.84 umol, 3.00 mL, 2.00 eq) wasadded to the resuidue. The resulting mixture was stirred at at 30° C.for 20 min. LCMS showed about 72% of desired product was detected. Themixture was concentrated under reduced pressure to remove solvent toafford compound 4 (30.00 mg, crude, HCl) as yellow oil. The residue wasnot purified and used in the next step directly.

Preparation of Compound 707

A mixture of Compound 4 (30.00 mg, 125.15 umol, 1.00 eq) and TEA (75.98mg, 750.90 umol, 104.08 uL, 6.00 eq) in DCM (3.00 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 30° C.for 16 h under N₂ atmosphere. LCMS showed desired product was detected.The mixture was adjusted to pH=3 and concentrated under reduced pressureto remove solvent. The residue was purified by prep-HPLC(FA) to affordCompound 707 as white solid. LCMS: 393/395[M+1].

Example 51: Preparation of Compounds 708, 712, 715, and 769

Step 1: Preparation of Compound 2

A mixture of compound 1 (1.00 eq), B₂Pin₂ (1.50 eq), KOAc (2.50 eq) andPd(dppf)Cl₂ (0.05 eq) in dioxane (5.00 mL) were heated to 100 under N₂for 16 hrs. TLC indicated starting material was consumed completely. Themixture was concentrated. The residue was purified by silica gel columnto afford Compound 2.

Preparation of Compounds 708, 712, 715, or 769

A mixture of compound 2 (2.50 eq), compound 3 (1.00 eq), Na₂CO₃ (2.50eq), XPhos (0.10 eq) and Pd₂(dba)₃ (0.05 eq) in dioxane/H₂O (10:1) werestirred at 100° C. under N₂ for 16 h. LCMS indicated the startingmaterial was consumed completely and desired product was detected. Themixture was diluted with EA and washed with brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby silica gel and repurified by prep-HPLC(FA) to afford Compounds 708,712, 715, or 769.

Structure Comp. ID Analytical Data

708 LCMS (M + 1): 373/375.

712 LCMS (M + 1): 373/375.

715 LCMS (M + 1): 384/386. ¹H NMR (400 MHz, METHANOL- d₄) ppm 7.94 (brs,1 H), 7.51 (s, 1 H), 7.42 (d, J = 5.02 Hz, 1 H), 7.26- 7.33 (m, 1 H),7.19-7.25 (m, 1 H), 7.00 (d, J = 8.03 Hz, 1 H), 4.72 (s, 2 H), 3.89 (t,J = 5.77 Hz, 2 H), 2.91 (t, J = 5.77 Hz, 2 H).

769 LCMS (M + 1): 389/391.

Example 52: Preparation of Compounds 716 and 766

Step 1: Preparation of Compound 3

To a mixture of Compound 1 (500.00 mg, 2.62 mmol, 1.00 eq) and compound2 (997.98 mg, 3.93 mmol, 1.50 eq) in dioxane (10.00 mL) was addedPd(dppf)Cl₂ (95.85 mg, 131.00 umol, 0.05 eq) and KOAc (514.25 mg, 5.24mmol, 2.00 eq), the reaction mixture was warmed to 100° C. and stirredat 100° C. for 3 hours under N₂. TLC (Petroleum ether:Ethylacetate=10:1) indicated compound 1 was consumed completely and one majornew spot with larger polarity was detected. Evaporated the solutionunder reduced pressure using a rotary evaporator. The residue waspurified by silica gel chromatography (200-300 mesh silica gel,Petroleum ether/Ethyl acetate=10/1 to 3/1) to afford Compound 3 (1.00 g,crude) as yellow oil.

Preparation of Compound 716

A mixture of compound 4 (150.00 mg, 421.80 umol, 1.00 eq), compound 3(110.48 mg, 463.98 umol, 1.10 eq) and XPhos (20.11 mg, 42.18 umol, 0.10eq) in dioxane (5.00 mL) and H₂O (750.00 uL) was degassed and purgedwith N₂ for 3 times. Pd₂(dba)₃ (19.31 mg, 21.09 umol, 0.05 eq) was addedto the mixture. The resulting mixture was stirred at 80° C. for 15 h.LC-MS showed desired compound was detected, and the compound 4 wasremained. Then another bacth of compound 3 (110.48 mg, 463.98 umol, 1.10eq) was added to the reaction mixture. The resulting mixture was stirredat 80° C. for 5 h. TLC showed desired product was detected. The mixturewas diluted with water (15 mL) and extracted by EtOAc (3*15 mL). Thecombined organic phases was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by prep-TLC(Dichloromethane:Methanol=20:1) to afford Compound 716 (113.00 mg,crude) as yellow solid. LCMS: 387/389 [M+1].

Preparation of Compound 766

A mixture of Compound 716 (113.00 mg, 292.10 umol, 1.00 eq) and NaBH₄(22.10 mg, 584.20 umol, 2.00 eq) in MeOH (4.00 mL) was stirred at 30° C.for 1 h. LCMS indicated about 88% of desired compound was detected. Thereaction mixture was added 10 drops of water and stirred for 10 min. Thereaction mixture was filtered. The reaction mixture was purified byprep-HPLC(FA) and re-purified by prep-TLC (Dichloromethane:Methanol20:1, Rf=0.2) to afford Compound 766 as white solid. LCMS: 411/413[M+23].

Example 53: Preparation of Compound 747

Step 1: Preparation of Compound 2

To a mixture of 2-chloro-3-fluoro-pyridine-4-carboxylic acid (3.00 g,17.09 mmol, 1.00 eq) in t-BuOH (20.00 mL) was added DPPA (7.05 g, 25.64mmol, 1.50 eq) and TEA (3.46 g, 34.18 mmol, 2.00 eq), the reactionmixture was warmed to 80° C. and stirred at 80° C. for 16 hours. Severalnew peaks were shown on LCMS and 20% of desired compound was detected.The mixture was extracted with EA (80 mL*3) and water (50 mL*2), theorganic phase was dried with anhydrous Na₂SO₄, filtered and concentratedin vacuum. The residue was purified by silica gel chromatography(200-300 mesh silica gel, Petroleum ether/Ethyl acetate=20/1 to 5/1) toafford tert-butyl N-(2-chloro-3-fluoro-4-pyridyl)carbamate (1.70 g, 5.86mmol, 34.28% yield, 85% purity) as yellow oil. LCMS: 247/249 [M+1].

Step 2: Preparation of Compound 3

To a mixture of tert-butyl N-(2-chloro-3-fluoro-4-pyridyl)carbamate(1.00 g, 4.05 mmol, 1.00 eq) in DMF (8.00 mL) was added Zn(CN)₂ (952.04mg, 8.10 mmol, 514.62 uL, 2.00 eq), Zn (52.97 mg, 810.00 umol, 0.20 eq),DPPF (898.98 mg, 1.62 mmol, 0.40 eq) and Pd₂(dba)₃ (742.47 mg, 810.00umol, 0.20 eq), and the reaction mixture was stirred at 120° C. for 16hours under N₂. TLC indicated starting material was consumed completelyand many new spots formed. The mixture was extracted with EA (20 mL*3)and water (10 mL*2), the organic phase was dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by silicagel chromatography (200-300 mesh silica gel, Petroleum ether/Ethylacetate=10/1 to 1/1) to afford 4-amino-3-fluoro-pyridine-2-carbonitrile(75.00 mg, 547.01 umol, 13.51% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 7.96-7.97 (d, J=5.52 Hz, 1H), 6.91-6.94 (dd, J=7.53, 5.40 Hz,1H), 6.86 (brs, 2H). LCMS: 138 [M+1].

Step 3: Preparation of Compound 5

To a mixture of 4-amino-3-fluoro-pyridine-2-carbonitrile (25.00 mg,182.34 umol, 1.00 eq) in CH₃CN (2.00 mL) was added TEA (36.90 mg, 364.68umol, 50.55 uL, 2.00 eq), compound 4(28.55 mg, 1.00 eq) and DMAP (2.23mg, 18.23 umol, 0.10 eq), the reaction mixture was stirred at 30° C. for16 hours. TLC indicated compound 3 was consumed completely, and onemajor new spot with lower polarity was detected. The mixture wasextracted with EA (10 mL*3) and water (10 mL), the organic phase wasdried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.Further purification by prep-TLC to afford phenylN-(2-cyano-3-fluoro-4-pyridyl)carbamate (23.00 mg, 74.22 umol, 40.70%yield, 83% purity) as white solid. LCMS: 258 [M+1].

Preparation of Compound 747

To a solution of phenyl N-(2-cyano-3-fluoro-4-pyridyl)carbamate (20.00mg, 77.75 umol, 1.00 eq) in DCM (2.00 mL) was added TEA (23.60 mg,233.25 umol, 32.33 uL, 3.00 eq) and3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (18.33 mg, 77.75umol, 1.00 eq, HCl), the reaction mixture was stirred at 25° C. for 2hours. LCMS showed compound 5 was consumed completely and one main peakwith desired MS was detected. The mixture was extracted with DCM (10mL*3) and water (10 mL), the organic phase was dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. Further purification byprep-HPLC(FA) to afford Compound 747 (8.00 mg, 21.92 umol, 28.19% yield,99.3% purity) as white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.31-8.32 (d,J=5.40 Hz, 1H), 7.95-7.98 (t, J=6.02 Hz, 1H), 7.61-7.63 (d, J=7.28 Hz,2H), 7.45-7.48 (t, J=6.90 Hz, 2H), 7.34-7.36 (d, J=7.03 Hz, 1H), 4.76(s, 2H), 3.79-3.82 (t, J=5.65 Hz, 2H), 2.78 (brs, 2H). LCMS: 363 [M+1].

Example 54: Preparation of Compound 756

Step 1: Preparation of Compound 2

To a mixture of 1-tert-butyl 2-methyl4-hydroxypyrrolidine-1,2-dicarboxylate (4.00 g, 16.31 mmol, 1.00 eq) inDCM (20.00 mL) was added Dess-Martin (8.30 g, 19.57 mmol, 1.20 eq) inone portion at 0° C. under N₂. The mixture was stirred at 20° C. for 5hours. TLC (Petroleum ether:Ethyl acetate=3:1) showed the reaction wascompleted. The reaction was quenched by Na₂S20₃ slowly and thenextracted with DCM (50 mL*2). The combined organic phase was washed withbrine (40 mL*2), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by silica gel chromatography(Petroleum ether/Ethyl acetate=10/1) to afford 1-tert-butyl 2-methyl4-oxopyrrolidine-1,2-dicarboxylate (3.70 g, 14.60 mmol, 89.53% yield,96% purity) as yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 4.66-4.89(m, 1H), 3.85-3.97 (m, 2H), 3.77 (s, 3H), 2.85-3.06 (m, 1H), 2.53-2.66(m, 1H), 1.48 (d, J=7.78 Hz, 9H). LCMS: 244[M+1].

Step 2: Preparation of Compounds 3 and 3A

To a mixture of 1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate(1.00 g, 4.11 mmol, 1.00 eq) and ethyl 2-diazoacetate (1.41 g, 12.33mmol, 1.29 mL, 3.00 eq) in Et₂O (10.00 mL) was added BF₃.Et₂O (1.75 g,12.33 mmol, 1.52 mL, 3.00 eq) dropwise at −45° C. under N₂. The mixturewas stirred at −45° C. for 30 min, then warmed to 20° C. and stirred for10 hours. TLC (Petroleum ether:Ethyl acetate=3:1) showed the desiredproduct was detected. The mixture was poured into saturated NaHCO₃ (20mL) and stirred for 3 min. The aqueous phase was extracted with ethylacetate (20 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by silica gel chromatography (Petroleumether/Ethyl acetate=15/1) to afford a mixture of 1-tert-butyl 4-ethyl2-methyl 5-oxopiperidine-1,2,4-tricarboxylate and 1-tert-butyl 5-ethyl2-methyl 4-oxopiperidine-1,2,5-tricarboxylate (400.00 mg, 1.21 mmol,29.44% yield) as yellow oil. LCMS: 330[M+1].

Step 3: Preparation of Compounds 4 and 4A

To a mixture of 1-tert-butyl 4-ethyl 2-methyl5-oxopiperidine-1,2,4-tricarboxy late and 1-tert-butyl 5-ethyl 2-methyl4-oxopiperidine-1,2,5-tricarboxylate (670.00 mg, 2.03 mmol, 1.00 eq) inMeOH (10.00 mL) was added N₂H4.H₂O (131.79 mg, 2.24 mmol, 127.96 uL, 85%purity, 1.10 eq) in one portion under N₂. The mixture was stirred at 20°C. for 12 hours. LCMS showed the reaction was completed. The mixture wasconcentrated in vacuum to afford a mixture of 6-tert-butyl 5-methyl3-hydroxy-1,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-5,6-dicarboxylateand 5-tert-butyl 6-methyl3-hydroxy-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5,6-dicarboxylate(600.00 mg, 2.02 mmol, 99.41% yield) as yellow solid. LCMS: 298[M+1].

Step 4: Preparation of Compounds 5 and 5A

To a mixture of 6-tert-butyl5-methyl-3-hydroxy-1,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-5,6-dicarboxylate and 5-tert-butyl6-methyl-3-hydroxy-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5,6-dicarboxylate (600.00 mg, 2.02 mmol, 1.00eq) in Py (10.00 mL) was added1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methane sulfonamide(1.08 g, 3.03 mmol, 1.50 eq) in one portion under N₂. The mixture wasstirred at 20° C. for 12 hours. TLC (Petroleum ether:Ethyl acetate=3:1)showed the reaction was completed. The mixture was concentrated invacuum. The residue was poured into 1 N HCl (30 mL) and stirred for 1min. The aqueous phase was extracted with ethyl acetate (20 mL*2). Thecombined organic phase was washed with brine (20 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by silica gel chromatography (Petroleum ether/Ethylacetate=15/1, 10/1) to afford 5-tert-butyl6-methyl-3-(trifluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5,6-dicarboxylate(120.00 mg, 279.48 umol, 13.84% yield) as yellow solid and6-tert-butyl-5-methyl-3-(trifluoromethylsulfonyloxy)-1,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-5,6-dicarboxylate (240.00 mg, 558.96 umol, 27.67% yield)as yellow solid. LCMS: 430[M+1].

Step 5: Preparation of Compound 6

To a mixture of 5-tert-butyl 6-methyl3-(trifluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5,6-dicarboxylate(100.00 mg, 232.90 umol, 1.00 eq) and phenylboronic acid (42.60 mg,349.35 umol, 1.50 eq) in dioxane (5.00 mL) and H₂O (500.00 uL) was addedXPHOS-PD-G2 (18.32 mg, 23.29 umol, 0.10 eq), K₃PO₄ (98.88 mg, 465.80umol, 2.00 eq) in one portion under N₂. The mixture was stirred at 110°C. for 10 hour. TLC (Ethyl acetate:Petroleum ether=2:1) showed thereaction was completed and the desired product was detected. The mixturewas poured into water (30 mL) and stirred for 2 min. The aqueous phasewas extracted with ethyl acetate (30 mL*2). The combined organic phasewas washed with brine (30 mL*2), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by silica gelchromatography (Petroleum ether/Ethyl acetate=5/1) to afford5-tert-butyl 6-methyl3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5,6-dicarboxylate(40.00 mg, 105.20 umol, 45.17% yield, 94% purity) as yellow solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.51-7.62 (m, 2H), 7.42-7.50 (m, 2H),7.33-7.42 (m, 1H), 5.27-5.43 (m, 1H), 4.47-4.55 (m, 1H), 4.36-4.44 (m,1H), 4.06-4.14 (m, 1H), 3.65-3.71 (m, 3H), 3.37 (d, J=4.39 Hz, 1H),2.99-3.14 (m, 1H), 1.51 (d, J=6.15 Hz, 9H). LCMS: 358[M+1].

Step 6: Preparation of Compound 7

To a mixture of 5-tert-butyl 6-methyl3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5,6-dicarboxylate(40.00 mg, 111.92 umol, 1.00 eq) in THF (5.00 mL) was added LiAlH₄(21.24 mg, 559.60 umol, 5.00 eq) in one portion at 0° C. under N₂. Themixture was stirred at 0° C. for 5 hours. LCMS and TLC (Ethylacetate:Petroleum ether=3:1) showed the reaction was completed. Themixture was poured into water (10 mL) and stirred for 5 min. The aqueousphase was extracted with ethyl acetate (10 mL*2). The combined organicphase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byprep-TLC (Petroleum ether/Ethyl acetate=1/4) to afford tert-butyl6-(hydroxymethyl)-3-phenyl-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate (20.00 mg, 60.72 umol, 54.25% yield) as yellowsolid. LCMS: 330[M+1].

Step 7: Preparation of Compound 8

To a mixture of tert-butyl6-(hydroxymethyl)-3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (10.00 mg, 30.36 umol, 1.00 eq) in dioxane(2.00 mL) was added HCl/dioxane (4 M, 4.00 mL, 527.01 eq) in one portionunder N₂. The mixture was stirred at 20° C. for 2 hours. TLC (Ethylacetate:Petroleum ether=3:1) showed the reaction was completed. Themixture was concentrated to afford(3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] pyridin-6-yl)methanol(8.07 mg, 30.37 umol, 100.00% yield, HCl) as yellow solid.

Preparation of Compound 756

To a mixture of(3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-6-yl)methanol(8.07 mg, 30.37 umol, 1.00 eq, HCl) and phenylN-(3-chlorophenyl)carbamate (7.52 mg, 30.37 umol, 1.00 eq) in DCM (5.00mL) was added TEA (7.68 mg, 75.92 umol, 10.52 uL, 2.50 eq) in oneportion under N₂. The mixture was stirred at 20° C. for 12 hours. LCMSshowed the reaction was completed. The mixture was poured into water (10mL) and stirred for 2 min. The aqueous phase was extracted with ethylacetate (10 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-HPLC (FA) to affordN-(3-chlorophenyl)-6-(hydroxylmethyl)-3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(9.33 mg, 24.25 umol, 79.84% yield, 99.5% purity) as white solid. ¹H NMR(400 MHz, METHANOL-d₄) δ 7.62-7.70 (m, 1H), 7.42-7.56 (m, 2H), 7.27-7.41(m, 2H), 7.19-7.26 (m, 1H), 6.98-7.03 (m, 1H), 5.05 (d, J=15.31 Hz, 2H),4.47 (d, J=15.43 Hz, 1H), 3.54-3.69 (m, 2H), 2.99-3.08 (m, 1H),2.86-2.94 (m, 1H). LCMS: 383/385[M+1].

Example 55: Preparation of Compound 754

Step 1: Preparation of Compound 2

To a mixture of 4-hydroxy-6-methyl-pyridine-3-carboxylic acid (5.00 g,32.65 mmol, 1.00 eq) in MeOH (60.00 mL) was added SOCl₂ (23.31 g, 195.90mmol, 6.00 eq) at 0° C. under N₂. The mixture was stirred at 0° C. for30 min, then heated to 80° C. and stirred for 10 hours. TLC(Dichloromethane:Methanol=5:1) showed the reaction was completed. Themixture was cooled to 20° C. and concentrated in vacuum to afford methyl4-hydroxy-6-methyl-pyridine-3-carboxylate (5.50 g, crude, HCl) as yellowsolid. LCMS: 168[M+1].

Step 2: Preparation of Compound 3

To a solution of methyl 4-hydroxy-6-methyl-pyridine-3-carboxylate (8.00g, 39.29 mmol, 1.00 eq, HCl) in AcOH (50.00 mL) was added PtO₂ (1.34 g,5.89 mmol, 0.15 eq) under N₂. The suspension was degassed under vacuumand purged with H₂ several times. The mixture was stirred under H₂ (50psi) at 60° C. for 24 hours. LCMS showed desired compound was detected.The reaction mixture was filtered and the filter was concentrated toafford methyl 4-hydroxy-6-methyl-piperidine-3-carboxylate (9.50 g,crude, AcOH salt) as yellow oil. LCMS: 174 [M+1].

Step 3: Preparation of Compound 4

To a mixture of methyl 4-hydroxy-6-methyl-piperidine-3-carboxylate (3.00g, 12.86 mmol, 1.00 eq, HOAC) and NaHCO₃ (1.62 g, 19.29 mmol, 750.00 uL,1.50 eq) in THF (10.00 mL) and H₂O (10.00 mL) was added Boc₂O (3.37 g,15.43 mmol, 3.55 mL, 1.20 eq) at 0° C. under N₂. The mixture was stirredat 25° C. for 5 hours. LCMS and TLC (Petroleum ether:Ethyl acetate=3:1)showed the reaction was completed. The mixture was extracted with ethylacetate (30 mL*2). The combined organic phase was washed with brine (20mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by silica gel chromatography (Petroleumether/Ethyl acetate=15/1) to afford 1-tert-butyl 3-methyl4-hydroxy-6-methyl-piperidine-1,3-dicarboxylate (1.50 g, 5.49 mmol,42.68% yield) as yellow oil. LCMS: 274[M+1].

Step 4: Preparation of Compound 5

To a mixture of 1-tert-butyl 3-methyl4-hydroxy-6-methyl-piperidine-1,3-dicarboxylate (1.50 g, 5.49 mmol, 1.00eq) in DCM (50.00 mL) was added Dess-Martin (2.79 g, 6.59 mmol, 2.04 mL,1.20 eq) in one portion at 0° C. under N₂. The mixture was stirred at 0°C. for 5 hours. TLC (Petroleum ether:Ethyl acetate=5:1) showed thereaction was completed. The reaction was quenched by Na₂S20₃ slowly andthen extracted with DCM (30 mL*2). The combined organic phase was washedwith brine (30 mL*2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (Petroleum ether/Ethyl acetate=20/1) to afford1-tert-butyl 3-methyl 6-methyl-4-oxo-piperidine-1,3-dicarboxylate (1.00g, 3.69 mmol, 67.14% yield) as yellow oil. ¹H NMR (300 MHz,CHLOROFORM-d) δ 11.99 (s, 1H), 4.53-4.69 (m, 1H), 4.46 (d, J=16.77 Hz,1H), 3.80 (s, 3H), 3.54-3.72 (m, 1H), 2.60-2.78 (m, 1H), 2.26-2.46 (m,1H), 1.44-1.52 (m, 11H), 1.15 (d, J=6.78 Hz, 3H). LCMS: 272[M+1].

Step 5: Preparation of Compound 6

To a mixture of 1-tert-butyl 3-methyl6-methyl-4-oxo-piperidine-1,3-dicarboxylate (2.50 g, 9.21 mmol, 1.00 eq)in MeOH (10.00 mL) was added N₂H4-H₂O (705.14 mg, 11.97 mmol, 684.60 uL,85% purity, 1.30 eq) in one portion under N₂. The mixture was stirred at75° C. for 2 hours. TLC (Petroleum ether:Ethyl acetate=4:1) showed thereaction was completed. The mixture was concentrated in vacuum to affordtert-butyl3-hydroxy-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(2.40 g, crude) as yellow solid, which was separated by SFC (Column:IC(250 mm*30 mm,10 um), Condition: Base-MeOH) to afford two enantiomers(E1: 1.0 g; E2: 1.1 g). ¹H NMR (300 MHz, METHANOL-d₄) δ 4.72-4.81 (m,1H), 4.58-4.68 (m, 1H), 3.75-3.88 (m, 1H), 2.75-2.87 (m, 1H), 2.37-2.49(m, 1H), 1.48 (d, J=1.13 Hz, 10H), 1.13 (d, J=6.78 Hz, 3H). LCMS:254[M+1].

Preparation of Compound 7(S)

To a mixture of tert-butyl 3-hydroxy-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (1.00 g, 3.95 mmol, 1.00 eq) in Py (15.00mL) was added1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(1.98 g, 5.53 mmol, 1.40 eq) in one portion under N₂. The mixture wasstirred at 20° C. for 12 hours. TLC showed the reaction was completed.The mixture was concentrated in vacuum. The residue was diluted withethyl acetate (50 mL) and poured into 0.5N HCl (20 mL) and stirred for 1min. The aqueous phase was extracted with ethyl acetate (50 mL*2). Thecombined organic phase was washed with brine (40 mL*2), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by silica gel chromatography (Petroleum ether/Ethylacetate=10/1) to afford tert-butyl6-methyl-3-(trifluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(850.00 mg, 2.21 mmol, 55.84% yield) as yellow solid. LCMS: 386[M+1].

Preparation of Compound 7(R)

To a mixture oftert-butyl-3-hydroxy-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (1.10 g, 4.34 mmol, 1.00 eq) in Py (15.00 mL) wasadded 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (2.17 g, 6.08 mmol, 1.40 eq) in one portion under N₂.The mixture was stirred at 20° C. for 12 hours. TLC showed the reactionwas completed. The mixture was concentrated in vacuum. The residue wasdiluted with ethyl acetate (60 mL) and poured into 0.5N HCl (20 mL) andstirred for 1 min. The aqueous phase was extracted with ethyl acetate(50 mL*2). The combined organic phase was washed with brine (50 mL*2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography (Petroleum ether/Ethylacetate=10/1) to affordtert-butyl6-methyl-3-(trifluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(920.00 mg, 2.39 mmol, 55.01% yield) as yellow solid. LCMS: 386[M+1].

Preparation of Compound 9

To a mixture of tert-butyl6-methyl-3-(trifluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(60.00 mg, 155.70 umol, 1.00 eq) and 3-thienylboronic acid (29.88 mg,233.55 umol, 1.50 eq) in dioxane (2.00 mL) and H₂O (200.00 uL) was added[2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (12.25 mg,15.57 umol, 0.10 eq) and K₃PO₄ (99.15 mg, 467.10 umol, 3.00 eq) in oneportion under N₂. The mixture was stirred at 110° C. for 12 hours. TLC(Petroleum ether:Ethyl acetate=1:1) showed the reaction was completed.The mixture was poured into water (10 mL) and stirred for 2 min. Theaqueous phase was extracted with ethyl acetate (10 mL*2). The combinedorganic phase was washed with brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byprep-TLC (Petroleum ether/Ethyl acetate=1/1) to afford tert-butyl6-methyl-3-(3-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (43.80 mg, 137.12 umol, 88.07% yield, 100%purity) as yellow solid. LCMS: 320[M+1].

Preparation of Compound 10

To a mixture of tert-butyl6-methyl-3-(3-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (43.80 mg, 137.12 umol, 1.00 eq) indioxane (3.00 mL) was added HCl/dioxane (4 M, 8.00 mL, 233.37 eq) in oneportion under N₂. The mixture was stirred at 20° C. for 2 hours. TLC(Petroleum ether:Ethyl acetate=1:1) showed the reaction was completed.The mixture was concentrated in vacuum to afford6-methyl-3-(3-thienyl)-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c]pyridine(35.07 mg, 137.12 umol, 100.00% yield, HCl) as yellow solid.

Preparation of Compound 754 (E1)

To a mixture of6-methyl-3-(3-thienyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(35.07 mg, 137.12 umol, 1.00 eq, HCl) and phenylN-(3-chlorophenyl)carbamate (33.96 mg, 137.12 umol, 1.00 eq) in DCM(5.00 mL) was added TEA (41.62 mg, 411.35 umol, 57.02 uL, 3.00 eq) inone portion under N₂. The mixture was stirred at 20° C. for 12 hours.LCMS showed the reaction was completed. The mixture was poured intowater (10 mL) and stirred for 2 min. The aqueous phase was extractedwith DCM (10 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-HPLC (FA) to affordN-(3-chlorophenyl)-6-methyl-3-(3-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(23.00 mg, 60.39 umol, 44.04% yield, 97.9% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.65-7.70 (m, 1H), 7.51-7.57 (m, 3H),7.29-7.34 (m, 1H), 7.20-7.28 (m, 1H), 6.99-7.05 (m, 1H), 4.99-5.06 (m,1H), 4.42 (d, J=15.18 Hz, 1H), 3.05 (s, 1H), 2.65-2.74 (m, 1H), 1.23 (d,J=6.90 Hz, 3H). LCMS: 373/375[M+1].

Preparation of Compound 11

To a mixture of tert-butyl6-methyl-3-(trifluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (60.00 mg, 155.70 umol, 1.00 eq)and 3-thienylboronic acid (29.88 mg, 233.55 umol, 1.50 eq) in dioxane(2.00 mL) and H₂O (200.00 uL) was added[2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (12.25 mg,15.57 umol, 0.10 eq) and K₃PO₄ (99.15 mg, 467.10 umol, 3.00 eq) in oneportion under N₂. The mixture was stirred at 110° C. for 12 hours. TLC(Petroleum ether:Ethyl acetate=1:1) showed the reaction was completed.The mixture was poured into water (10 mL) and stirred for 2 min. Theaqueous phase was extracted with ethyl acetate (10 mL*2). The combinedorganic phase was washed with brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byprep-TLC (Petroleum ether/Ethyl acetate=1/1) to afford tert-butyl6-methyl-3-(3-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (42.20 mg, 132.11 umol, 84.85% yield, 100%purity) as yellow solid. LCMS: 320[M+1].

Preparation of Compound 12

To a mixture of tert-butyl6-methyl-3-(3-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (42.00 mg, 131.49 umol, 1.00 eq) indioxane (3.00 mL) was added HCl/dioxane (4 M, 8.00 mL, 243.36 eq) in oneportion under N₂. The mixture was stirred at 20° C. for 2 hours. TLC(Petroleum ether:Ethyl acetate=1:1) showed the reaction was completed.The mixture was concentrated in vacuum to afford6-methyl-3-(3-thienyl)-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c]pyridine(33.63 mg, 131.49 umol, 100.00% yield, HCl) as yellow solid.

Preparation of Compound 754 (E2)

To a mixture of6-methyl-3-(3-thienyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(33.63 mg, 131.49 umol, 1.00 eq, HCl) and phenylN-(3-chlorophenyl)carbamate (32.57 mg, 131.49 umol, 1.00 eq) in DCM(5.00 mL) was added TEA (39.91 mg, 394.46 umol, 54.68 uL, 3.00 eq) inone portion under N₂. The mixture was stirred at 20° C. for 12 hours.LCMS showed the reaction was completed. The mixture was poured intowater (10 mL) and stirred for 2 min. The aqueous layer was extractedwith DCM (10 mL*2). The combined organic phase was washed with brine (10mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-HPLC (FA) to affordN-(3-chlorophenyl)-6-methyl-3-(3-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(25.00 mg, 66.58 umol, 50.63% yield, 99.3% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.65-7.70 (m, 1H), 7.51-7.57 (m, 3H),7.29-7.34 (m, 1H), 7.20-7.28 (m, 1H), 6.99-7.05 (m, 1H), 4.99-5.06 (m,1H), 4.42 (d, J=15.18 Hz, 1H), 3.05 (s, 1H), 2.65-2.74 (m, 1H), 1.23 (d,J=6.90 Hz, 3H). LCMS: 373/375 [M+1].

Example 56: Preparation of Compounds 753, 819, 820, 821, 822, 823, 824,825, 826, 851, 852, 853, 854, 856, and 857

Step 1: Preparation of Compound 9

To a mixture of tert-butyl6-methyl-3-(trifluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (70.00 mg, 181.65 umol, 1.00 eq)and 2-thienylboronic acid (34.87 mg, 272.47 umol, 1.50 eq) in dioxane(1.00 mL) and H₂O (100.00 uL) was added[2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (14.29 mg,18.16 umol, 0.10 eq) and K₃PO₄ (115.68 mg, 544.94 umol, 3.00 eq) in oneportion under N₂. The mixture was stirred at 110° C. for 12 hours. TLC(Petroleum ether:Ethyl acetate=1:1) showed the reaction was completed.The mixture was poured into water (10 mL) and stirred for 2 min. Theaqueous phase was extracted with ethyl acetate (10 mL*2). The combinedorganic phase was washed with brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byprep-TLC (Petroleum ether/Ethyl acetate=1/1) to afford tert-butyl6-methyl-3-(2-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(10.00 mg, 31.31 umol, 17.23% yield, 100% purity) as yellow solid. LCMS:320[M+1].

Step 2: Preparation of Compound 10

To a mixture of tert-butyl6-methyl-3-(2-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (10.00 mg, 31.31 umol, 1.00 eq) in dioxane(2.00 mL) was added HCl/dioxane (4 M, 5.00 mL, 638.77 eq) in one portionunder N₂. The mixture was stirred at 20° C. 2 hours. TLC (Petroleumether:Ethyl acetate=1:1) showed the reaction was completed. The mixturewas concentrated in vacuum to afford6-methyl-3-(2-thienyl)-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c]pyridine(8.00 mg, 31.28 umol, 99.90% yield, HCl) as white solid.

Preparation of Compound 753 (E1)

To a mixture of 6-methyl-3-(2-thienyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (8.01 mg, 31.32 umol, 1.00 eq, HCl) and phenylN-(3-chlorophenyl)carbamate (7.76 mg, 31.32 umol, 1.00 eq) in DCM (5.00mL) was added TEA (12.68 mg, 125.28 umol, 17.37 uL, 4.00 eq) in oneportion under N₂. The mixture was stirred at 20° C. for 12 hours. LCMSshowed the reaction was completed. The mixture was poured into water (10mL) and stirred for 2 min. The aqueous phase was extracted with DCM (10mL*2). The combined organic phase was washed with brine (10 mL*1), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by prep-HPLC (FA) to affordN-(3-chlorophenyl)-6-methyl-3-(2-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(7.65 mg, 19.84 umol, 63.34% yield, 96.7% purity) as white solid. ¹H NMR(400 MHz, METHANOL-d₄) δ 7.53 (s, 1H), 7.29-7.46 (m, 3H), 7.21-7.27 (m,1H), 7.12-7.17 (m, 1H), 7.02 (d, J=8.41 Hz, 1H), 4.99-5.06 (m, 2H),4.33-4.44 (m, 1H), 3.02-3.13 (m, 1H), 2.65-2.75 (m, 1H), 1.22-1.26 (m,1H). LCMS: 373/375 [M+1].

Compounds 753 (E2), 819, 820, 821 through 826, and 851 through 857 wereprepared by the same method.

MS (M + Structure Comp. ID ¹H NMR H)⁺

753 (E2) ¹H NMR (400 MHz, METHANOL-d₄) δ 7.53 (s, 1 H), 7.29-7.46 (m, 3H), 7.21-7.27 (m, 1 H), 7.12-7.17 (m, 1 H), 7.02 (d, J = 8.41 Hz, 1 H),4.99- 5.06 (m, 2 H), 4.33- 4.44 (m, 1 H), 3.02-3.13 (m, 1 H), 2.65-2.75(m, 1 H), 1.22-1.26 (m, 1 H). 373/375

819 391/393

820 417/419

821 435/437

822 435/437

823 ¹H NMR (400 MHz, METHANOL-d₄) δ 7.99- 8.05 (m, 1 H), 7.77-7.84 (m, 1H), 7.40-7.49 (m, 1 H), 7.30-7.37 (m, 1 H), 7.11-7.18 (m, 1 H), 5.04 (d,J = 15.56 Hz, 2 H), 4.45 (d, J = 15.43 Hz, 1 H), 3.06-3.16 (m, 1 H),2.71 (d, J = 16.06 Hz, 1 H), 1.27 (d, J = 6.90 Hz, 3 H) 436/438

824 ¹H NMR (400 MHz, METHANOL-d₄) δ 7.81 (dd, J = 2.76, 5.65 Hz, 1 H),7.67-7.75 (m, 1 H), 7.36 (brs, 2 H), 7.28 (t, J = 8.97 Hz,1 H), 7.14(brs, 1 H), 4.96-5.07 (m, 2 H), 4.38 (d, J = 15.56 Hz, 1 H), 3.02-3.11(m, 1 H), 2.70 (d, J = 15.81 Hz, 1 H), 1.25 (d, J = 6.90 Hz, 3 H). 382

825 ¹H NMR (400 MHz, METHANOL-d₄) δ 7.31- 7.45 (m, 2 H), 7.17 (s, 4 H),6.83-6.90 (m, 1 H), 4.96-5.06 (m, 2 H), 4.31- 4.43 (m, 1 H), 3.01- 3.12(m, 1 H), 2.64-2.73 (m, 1 H), 2.31 (s, 3 H), 1.24 (d, J = 6.78 Hz, 3H).353

826 ¹H NMR (400 MHz, METHANOL-d₄) δ 7.32- 7.49 (m, 2 H), 7.21-7.26 (m, 1H), 7.10-7.19 (m, 2 H), 6.94 (t, J = 9.10 Hz, 1 H), 5.01 (d, J = 15.43Hz, 2 H), 4.31-4.39 (m, 1 H), 3.01-3.11 (m, 1 H), 2.65-2.72 (m, 1 H),2.24 (d, J = 1.51 Hz, 3 H), 1.23 (d, J = 6.90 Hz, 3 H). 371

857 ¹H NMR (400 MHz, METHANOL-d₄) δ 7.57- 7.62 (m, 1 H), 7.28-7.48 (m, 3H), 7.11-7.19 (m, 2 H), 5.00-5.07 (m, 2 H), 4.37 (d, J = 15.18 Hz, 1 H),3.00-3.10 (m, 1 H), 2.64-2.74 (m, 1 H), 1.24 (d, J = 6.78 Hz, 3 H).391/393

851 417/419

852 ¹H NMR (400 MHz, METHANOL-d₄) δ 7.69- 7.78 (m, 1 H), 7.31-7.50 (m, 3H), 7.06-7.20 (m, 2 H), 4.99-5.04 (m, 2 H), 4.31-4.43 (m, 1 H), 3.01-3.11 (m, 1 H), 2.65- 2.74 (m, 1 H), 1.24 (d, J = 6.90 Hz, 3 H). 435/437

853 436/438

854 ¹H NMR (400 MHz, METHANOL-d4) δ 7.76- 7.81 (m, 1 H), 7.65-7.69 (m, 1H), 7.30-7.40 (m, 2 H), 7.09-7.23 (m, 2 H) 4.92-5.05 (m, 2 H), 4.36-4.39 (m, 1 H), 3.00- 3.13 (m, 1 H), 2.57-2.77 (m, 1 H), 1.18-1.31 (m, 3H). 382

855 ¹H NMR (400 MHz, METHANOL-d4) δ 7.34- 7.47 (m, 1 H), 7.11-7.27 (m, 2H), 6.89-6.98 (m, 1 H), 5.01 (d, J = 15.18 Hz, 2 H), 4.32-4.40 (m, 1 H),3.01-3.10 (m, 1 H), 2.65- 2.72 (m, 1 H), 2.24 (d, J = 1.51 Hz, 3 H),1.23 (d, J = 6.78 Hz, 3 H). 371

856 391/393

Example 57: Preparation of Compound 830

To a mixture of 3-chloro-N-methyl-aniline (18.27 mg, 129.02 umol, 15.75uL, 1.10 eq) and TEA (35.61 mg, 351.87 umol, 48.78 uL, 3.00 eq) in DCM(2.00 mL) was added TRIPHOSGENE (27.85 mg, 93.83 umol, 0.80 eq) in oneportion at 0° C. under N₂. The mixture was stirred at 0° C. for 5 min.Then(6S)-6-methyl-3-(2-thienyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(30.00 mg, 117.29 umol, 1.00 eq, HCl) was added to the mixture, themixture was stirred at 0° C. for 30 min. LCMS showed the reaction wascompleted. The mixture was poured into water (10 mL) and stirred for 2min. The aqueous phase was extracted with DCM (10 mL*2). The combinedorganic phase was washed with brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byprep-HPLC (FA) to afford(6S)—N-(3-chlorophenyl)-N,6-dimethyl-3-(2-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(10.55 mg, 26.99 umol, 23.01% yield, 98.99% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.32-7.45 (m, 2H), 7.27-7.31 (m, 1H),7.02-7.24 (m, 4H), 4.67-4.74 (m, 1H), 4.50-4.57 (m, 1H), 3.77-3.85 (m,1H), 3.23 (s, 3H), 2.78 (d, J=5.27 Hz, 1H), 2.45-2.55 (m, 1H), 1.07-1.17(m, 3H). LCMS: 387/389[M+1].

Example 58: Preparation of Compounds 831 and 832

Step 1: Preparation of Compounds 4A and 4B

To a mixture of tert-butyl(6S)-6-methyl-3-(2-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-caboxylate (50.00 mg, 156.53 umol, 1.00 eq) inTH (2.00 mL) was added NaH (9.39 mg, 234.80 umol, 60% purity, 1.50 eq)in one portion at 0° C. under N₂. The mixture was stirred at 0° C. for30 min, then MeMe(66.66 mg, 469.60 umol, 29.23 uL, 3.00 eq) was added tothe mixture, The mixture was stirred at 0° C. for 1 hours. TLC(Petroleum ether:Ethyl acetate=2:1) showed the reaction was completed.The mixture was poured into water (10 mL) and stirred for 2 min. Theaqueous phase was extracted with ethyl acetate (10 mL*2). The combinedorganic phase was washed with brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byprep-TLC(Petroleum ether/Ethyl acetate=5/1, 10 times) to affordtert-butyl(6S)-1,6-dimethyl-3-(2-thienyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(20.00 mg, 59.98 umol, 38.32% yield) as yellow solid andtert-butyl(6S)-2,6-dimethyl-3-(2-thienyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(15.00 mg, 44.98 umol, 28.74% yield) as yellow solid.

Compound 4A: ¹H NMR (400 MHz, CHLOROFORM-d) 807.26-7.29 (m, 1H),7.16-7.21 (m, 1H), 7.06-7.11 (m, 1H), 4.76-5.12 (m, 2H), 4.08-4.22 (m,1H), 3.78 (s, 3H), 2.88-3.01 (m, 1H), 2.39-2.53 (m, 1H), 1.51 (s, 9H),1.18 (d, J=6.90 Hz, 3H). LCMS: 334[M+1].

Compound 4B: ¹H NMR (400 MHz, CHLOROFORM-d) 807.43-7.48 (m, 1H),7.14-7.18 (m, 1H), 7.13 (s, 1H), 4.72-4.99 (m, 2H), 3.99-4.09 (m, 1H),3.93 (s, 3H), 2.91-3.03 (m, 1H), 2.52-2.65 (m, 1H), 1.48 (s, 9H), 1.16(d, J=7.03 Hz, 3H). LCMS: 334[M+1].

Step 2A: Preparation of Compound 5A

To a mixture of tert-butyl(6S)-1,6-dimethyl-3-(2-thienyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (20.00 mg, 59.98 umol, 1.00 eq) in dioxane(2.00 mL) was added HCl/dioxane (4 M, 729.81 uL, 48.67 eq) in oneportion under N₂. The mixture was stirred at 30° C. for 2 hours. TLC(Petroleum ether:Ethyl acetate=3:1) showed the reaction was completed.The mixture was concentrated in vacuum to afford(6S)-1,6-dimethyl-3-(2-thienyl)-4,5,6,7-tetrahydropyrazolo [4,3-c]pyridine (16.18 mg, 59.97 umol, 100.00% yield, HCl) as white solid.

Preparation of Compound 831

To a mixture of(6S)-1,6-dimethyl-3-(2-thienyl)-4,5,6,7-tetrahydropyrazolo [4,3-c]pyridine (16.18 mg, 59.97 umol, 1.00 eq, HCl) and phenylN-(3-chlorophenyl)carbamate (14.85 mg, 59.97 umol, 1.00 eq) in DCM (5.00mL) was added TEA (18.21 mg, 179.92 umol, 24.94 uL, 3.00 eq) in oneportion under N₂. The mixture was stirred at 30° C. for 12 hours. LCMSshowed the reaction was completed. The mixture was poured into water (10mL) and stirred for 2 min. The aqueous phase was extracted with DCM (10mL*2). The combined organic phase was washed with brine (10 mL*2), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by prep-HPLC (FA) to afford(6S)—N-(3-chlorophenyl)-1,6-dimethyl-3-(2-thienyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide(10.00 mg, 25.56 umol, 42.62% yield, 98.9% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.51-7.54 (m, 1H), 7.36-7.39 (m, 1H),7.27-7.34 (m, 2H), 7.20-7.27 (m, 1H), 7.09-7.14 (m, 1H), 6.99-7.04 (m,1H), 4.98 (s, 2H), 4.31-4.38 (m, 1H), 3.78 (s, 3H), 2.97-3.06 (m, 1H),2.67-2.76 (m, 1H), 1.25 (d, J=6.90 Hz, 3H). LCMS: 387/389[M+1].

Step 2B: Preparation of Compound 5B

To a mixture of tert-butyl(6S)-2,6-dimethyl-3-(2-thienyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (15.00 mg, 44.98 umol, 1.00 eq) in dioxane(1.00 mL) was added HCl/dioxane (4 M, 4.00 mL, 355.71 eq) in one portionat 30° C. under N₂. The mixture was stirred at 30° C. for 2 hours. TLC(Petroleum ether:Ethyl acetate=3:1) showed the reaction was completed.The mixture was concentrated in vacuum to afford(6S)-2,6-dimethyl-3-(2-thienyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (12.14 mg, 45.00 umol, 100.00% yield, HCl) as yellow solid.

Preparation of Compound 832

To a mixture of(6S)-2,6-dimethyl-3-(2-thienyl)-4,5,6,7-tetrahydropyrazolo [4,3-c]pyridine (12.14 mg, 45.00 umol, 1.00 eq, HCl) and phenylN-(3-chlorophenyl)carbamate (11.15 mg, 45.00 umol, 1.00 eq) in DCM (3.00mL) was added TEA (13.66 mg, 134.99 umol, 18.71 uL, 3.00 eq) in oneportion at 30° C. under N₂. The mixture was stirred at 30° C. for 12hours. LCMS showed the reaction was completed. The mixture was pouredinto water (10 mL) and stirred for 3 min. The aqueous phase wasextracted with ethyl acetate (10 mL*2). The combined organic phase waswashed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by prep-HPLC (FA) toafford(6S)—N-(3-chlorophenyl)-2,6-dimethyl-3-(2-thienyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxamide(16.38 mg, 42.34 umol, 94.08% yield, 100% purity) as white solid. ¹H NMR(400 MHz, METHANOL-d₄) δ 7.64-7.69 (m, 1H), 7.48-7.51 (m, 1H), 7.30-7.34(m, 1H), 7.18-7.29 (m, 1H), 6.97-7.03 (m, 1H), 4.93 (d, J=6.15 Hz, 2H),4.22-4.30 (m, 1H), 3.91 (s, 3H), 2.98-3.07 (m, 1H), 2.60-2.69 (m, 1H),1.23 (d, J=6.78 Hz, 3H). LCMS: 387/389[M+1].

Example 59: Preparation of Compound 753 (S)

Step 1: Preparation of Compound 2

To a solution of (3S)-3-aminobutanoic acid (13.00 g, 93.14 mmol, 1.00eq, HCl) in EtOH (130.00 mL) was added SOCl₂ (16.62 g, 139.70 mmol,10.13 mL, 1.50 eq). The mixture was heated to 80° C. for 3 hr. Themixture was concentrated in vacuum to afford ethyl (3S)-3-aminobutanoate(15.60 g, 93.06 mmol, 99.92% yield, HCl) as brown oil.

Step 2: Preparation of Compound 3

To a solution of ethyl (3S)-3-aminobutanoate (15.60 g, 93.06 mmol, 1.00eq, HCl) in MeOH (150.00 mL) was added NaOH (4.47 g, 111.67 mmol, 1.20eq) followed by ethyl prop-2-enoate (10.25 g, 102.37 mmol, 11.14 mL,1.10 eq). The mixture was heated to 80° C. for 16 hr. The mixture wascooled to 0° C. and added Boc₂O (20.31 g, 93.06 mmol, 21.38 mL, 1.00 eq)followed by TEA (9.42 g, 93.06 mmol, 12.90 mL, 1.00 eq). The mixture wasstirred at 25° C. for 2 hr. The mixture was concentrated in vacuum. Theresidue was extracted with DCM (100 mL*2) and H₂O (100 mL). The combinedorganic layer was washed with 1N HCl(100 mL), dried over Na₂SO₄,filtrated. The filtrate was concentrated in vacuum. The residue waspurified by flash chromatography (PE:EA=0%-15%) to afford methyl(3S)-3-[tert-butoxycarbonyl-(3-methoxy-3-oxo-propyl)amino] butanoate(13.00 g, 42.85 mmol, 46.05% yield) as colorless oil. ¹H NMR (400 MHz,CHLOROFORM-d) δ 4.13 (q, J=7.2 Hz, 2H), 3.65-3.72 (m, 5H), 3.29-3.54 (m,2H), 2.51-2.73 (m, 3H), 2.47 (dd, J=6.8, 14.9 Hz, 1H), 1.43-1.49 (m,9H), 1.22-1.29 (m, 5H).

Step 3: Preparation of Compound 4

To a solution of methyl3S)-3-[tert-butoxycarbonyl-(3-methoxy-3-oxo-propyl)amino] butanoate(7.00 g, 23.08 mmol, 1.00 eq) in THF (200.00 mL) was added t-BuOK (2.85g, 25.38 mmol, 1.10 eq) at −40° C. The mixture was stirred at −40° C.for 0.5 hr. The mixture was quenched with NH₄Cl (100 mL) and extractedwith EA (200 mL). The organic layer was dried over Na₂SO₄, filtered. Thefiltrate was concentrated to afford 01-tert-butyl-O3-methyl(6S)-6-methyl-4-oxo-piperidine-1,3-dicarboxylate (5.80 g, 21.38 mmol,92.62% yield) as brown oil.

Step 4: Preparation of Compound 5

To a solution of O1-tert-butyl O3-methyl(6S)-6-methyl-4-oxo-piperidine-1,3-dicarboxylate (5.80 g, 21.38 mmol,1.00 eq) in EtOH (60.00 mL) was added NH₂NH₂.H₂O (2.52 g, 42.76 mmol,2.44 mL, 85% purity, 2.00 eq). The mixture was heated to 80° C. for 2hr. The mixture was concentrated in vacuum. The residue was extractedwith EA (100 mL*2) and H₂O (80 mL). The combined organic layer was driedover Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. Theresidue was purified by prep-HPLC (FA) to affordtert-butyl-(6S)-3-hydroxy-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(1.50 g, 5.80 mmol, 27.14% yield, 98% purity) as white solid.

Step 5: Preparation of Compound 6

To a solution oftert-butyl-(6S)-3-hydroxy-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(1.00 g, 3.95 mmol, 1.00 eq) in Py (10.00 mL) was added1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide(1.48 g, 4.15 mmol, 1.05 eq). The mixture was stirred at 25° C. for 16hr. The mixture was concentrated in vacuum and extracted with EA (100mL*2) and 1N HCl(50 mL). The combined organic layer was dried overNa₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residuewas purified by column chromatography PE:EA=10%-50% to afford tert-butyl(6S)-6-methyl-3-(triFluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (700.00 mg, 1.82 mmol, 45.99% yield) as whitesolid.

Step 6: Preparation of Compound 8

To a solution of tert-butyl(6S)-6-methyl-3-(trifluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate(50.00 mg, 129.75 umol, 1.00 eq) and 2-thienylboronic acid (24.90 mg,194.63 umol, 1.50 eq) in dioxane (2.00 mL) and H₂O (200.00 uL) was addedXPHOS-PD-G2 (10.21 mg, 12.98 umol, 0.10 eq) and K₃PO₄ (82.63 mg, 389.25umol, 3.00 eq). The mixture was heated to 100° C. for 16 hr. The mixturewas extracted with EA (30 mL*2) and H₂O (30 mL). The combined organiclayer was dried over Na₂SO₄, filtrated. The filtrate was concentrated invacuum. The residue was purified by prep-TLC (PE:EA=3:1) to affordtert-butyl (6S)-6-methyl-3-(2-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (30.00 mg, 93.92 umol, 72.39% yield) as whitesolid.

Step 7: Preparation of Compound 9

Tert-butyl (6S)-6-methyl-3-(2-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (30.00 mg, 93.92 umol, 1.00 eq) in DCM(2.00 mL) was added TFA (27.01 mmol, 2.00 mL, 287.62 eq). The mixturewas stirred at 25° C. for 1 hr. The mixture was concentrated in vacuumto afford(6S)-6-methyl-3-(2-thienyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(45.00 mg, crude, 2TFA) as brown oil.

Preparation of Compound 753(S)

To a solution of(6S)-6-methyl-3-(2-thienyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (42.00 mg, 93.89 umol, 1.00 eq, 2TFA) in DCM (5.00 mL) wasadded TEA (38.00 mg, 375.56 umol, 52.05 uL, 4.00 eq) followed by phenylN-(3-chlorophenyl)carbamate (23.25 mg, 93.89 umol, 1.00 eq). The mixturewas stirred at 25° C. for 16 hr. The mixture was concentrated in vacuum.The residue was purified by prep-HPLC (FA) to afford(6S)—N-(3-chlorophenyl)-6-methyl-3-(2-thienyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(16.00 mg, 42.65 umol, 45.43% yield, 99.4% purity) as white solid. ¹HNMR (400 MHz, METHANOL-d4) δ 7.55 (t, J=2.0 Hz, 1H), 7.36-7.50 (m, 2H),7.30-7.36 (m, 1H), 7.22-7.29 (m, 1H), 7.16 (t, J=4.1 Hz, 1H), 7.01-7.07(m, 1H), 4.95-5.11 (m, 2H), 4.39 (d, J=15.4 Hz, 1H), 3.09 (dd, J=5.8,16.3 Hz, 1H), 2.71 (d, J=15.9 Hz, 1H), 1.26 (d, J=6.9 Hz, 3H). LCMS:373/375[M+1].

Example 60: Preparation of Compounds 917, 918, 919, 920, 921, 922, 923,and 924 (E1 &E2)

Step 1: Preparation of Compound 2

Thiazole-4-carboxylic acid (6.00 g, 46.46 mmol, 1.00 eq) was dissolvedin SOCl₂ (100.00 mL) and heated to 80° C. for 2 hr. The mixture wasconcentrated in vacuum to afford thiazole-4-carbonyl chloride (7.00 g,crude) as yellow solid.

Step 2: Preparation of Compound 4

To a solution of tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate(9.60 g, 45.01 mmol, 1.00 eq) in THF (100.00 mL) was added LiHMDS (1 M,67.52 mL, 1.50 eq) dropwise at −70° C. The mixture was stirred at −70°C. for 0.5 hr. Thiazole-4-carbonyl chloride (6.64 g, 45.01 mmol, 1.00eq) in THF (60.00 mL) was added dropwise at −70° C. The mixtre wasstirred at −60° C. for 2 hr. The mixture was quenched by NH₄Cl (200 mL)and extracted with EA (500 mL*4). The combined organic layer was driedover Na₂SO₄ and filtrated. The filtrate was concentrated in vacuum toafford a mixture of tert-butyl2-methyl-4-oxo-3-(thiazole-4-carbonyl)piperidine-1-carboxylate andtert-butyl2-methyl-4-oxo-5-(thiazole-4-carbonyl)piperidine-1-carboxylate (13.00 g,crude) as black oil.

Step 3: Preparation of Compound 5

To a solution of a mixuture (13.00 g, 40.08 mmol, 1.00 eq) of tert-butyl2-methyl-4-oxo-3-(thiazole-4-carbonyl)piperidine-1-carboxylate andtert-butyl2-methyl-4-oxo-5-(thiazole-4-carbonyl)piperidine-1-carboxylate in EtOH(150.00 mL) was added NH2NH2.H2O (3.54 g, 60.12 mmol, 3.44 mL, 85%purity, 1.50 eq). The mixture was stirred at 25° C. for 8 hr. Themixture was concentrated in vacuum and extracted with EA (500 mL*5) andwater (300 mL). The combined organic layer was dried over Na₂SO₄, andfiltrated. The filtrate was concentrated in vacuum. The residue waspurified by flash chromatography (PE:EA=30%-100%) to afford a mixture(5.00 g, 15.61 mmol, 38.93% yield) of tert-butyl4-methyl-3-thiazol-4-yl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate and tert-butyl6-methyl-3-thiazol-4-yl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylateas yellow solid.

2.65 g of mixture were seperated by SFC (Column: AD-10 um; Mobile phase:A for CO2 and B for Isopropanol (0.1% NH3H2O); Isocratic: B 50%; Flowrate: 70 mL/min; Back pressure: 100 bar; Column temperature: 35° C.;Wavelength: 220 nm) to get a mixture (1.2 g) of peak one and peak twoand peak three (683 mg); peak four (559 mg). The resulting mixture (1.2g) of peak one and peak two was further separated by SFC (Instrument:SFC 80; Column: AD-10 um; Mobile phase: A for CO2 and B for Methanol(0.1% NH3H2O); Isocratic: B 35%; Flow rate: 65 mL/min.

Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 220 nm)to get peak one (500 mg) and peak two (650 mg).

Peak 1 and peak 4 were confirmed as both enantiomers of tert-butyl4-methyl-3-thiazol-4-yl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate5′ by H NMR, and peak 2 and peak 3 were both enantiomers of tert-butyl4-methyl-3-thiazol-4-yl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate 5.

5′_E1 (peak 1): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.91 (br. s., 1H),7.50 (d, J=1.6 Hz, 1H), 5.76-5.43 (m, 1H), 4.55-4.24 (m, 1H), 3.34-3.09(m, 1H), 2.94-2.70 (m, 2H), 1.63-1.36 (m, 12H)

5_E1 (peak 2): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.96 (d, J=1.8 Hz,1H), 7.44 (d, J=1.9 Hz, 1H), 5.20-5.06 (m, 1H), 4.89 (br. s., 1H), 4.26(d, J=15.8 Hz, 1H), 3.05 (dd, J=5.9, 15.7 Hz, 1H), 2.68 (d, J=15.7 Hz,1H), 1.53 (s, 9H), 1.19 (d, J=6.9 Hz, 3H)

5_E2 (peak 3): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.96 (d, J=1.6 Hz,1H), 7.44 (d, J=1.5 Hz, 1H), 5.13 (d, J=15.1 Hz, 1H), 4.90 (br. s, 1H),4.26 (d, J=15.9 Hz, 1H), 3.05 (dd, J=5.9, 15.7 Hz, 1H), 2.68 (d, J=15.7Hz, 1H), 1.53 (s, 9H), 1.19 (d, J=6.9 Hz, 3H).

5′_E2 (peak 4): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.93 (br. s, 1H),7.51 (s, 1H), 5.75-5.49 (m, 1H), 4.54-4.24 (m, 1H), 3.31-3.10 (m, 1H),2.91-2.73 (m, 2H), 1.53 (s, 9H), 1.43 (d, J=6.5 Hz, 3H).

Step 4: Preparation of Compound 6 (E1)

Tert-butyl6-methyl-3-thiazol-4-yl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate 5_E1 (650.00 mg, 2.03 mmol, 1.00 eq) wasdissolved in HCl/dioxane (4 M, 15.00 mL, 29.56 eq) and stirred at 25° C.for 2 hr. The mixture was concentrated in vacuum to afford4-(6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c]pyridin-3-yl) thiazole(602.00 mg, crude, 2 HCl) as white solid.

General Preparation of Compounds 917 through 924 (E1&E2)

(Compound 917 (E1) as Example)

To a mixture of4-(6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl) thiazole(40.00 mg, 136.42 umol, 1.00 eq, 2 HCl) in DCM (2.00 mL) was added TEA(41.41 mg, 409.26 umol, 56.73 uL, 3.00 eq), followed by phenylN-(3-chloro-4-fluoro-phenyl)carbamate (36.24 mg, 136.42 umol, 1.00 eq),the reaction mixture was stirred at 25° C. for 16 hours. LCMS showed thestarting material consumed completely and the desired product wasdetected. The solvent was remoced on a rotary evaporator, and theresidue was purified by prep-HPLC(FA) to giveN-(3-chloro-4-fluoro-phenyl)-6-methyl-3-thiazol-4-yl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(43.00 mg, 109.30 umol, 80.12% yield, 99.6% purity) as white solid.

Structure Comp. ID Analytical Data

0917 (E1) LCMS (M + 1): 392 917 (E2) LCMS (M + 1): 392.0

918 (E1) LCMS (M + 1): 418,420 ¹H NMR (400 MHz, METHANOL-d4) d ppm 9.10(d, J = 2.01 Hz, 1 H) 7.84 (d, J = 1.88 Hz, 1 H) 7.67- 7.71 (m, 1 H)7.37 (dt, J = 7.12, 2.02 Hz, 1 H) 7.13-7.22 (m, 2 H) 5.15 (d, J = 15.81Hz, 1 H) 4.99 (quin, J = 6.43 Hz, 1 H) 4.47 (d, J = 15.81 Hz, 1 H) 3.07(dd, J = 15.87, 5.71 Hz, 1 H) 2.71 (d, J = 15.81 Hz, 1 H) 1.23 (d, J =6.78 Hz, 3 H) 918 (E2) LCMS (M + 1): 418.0

919 (E1) LCMS (M + 1): 436,438 ¹H NMR (400 MHz, METHANOL-d4) d ppm 9.09(d, J = 1.88 Hz, 1 H) 7.83 (d, J = 1.88 Hz, 1 H) 7.74 (dd, J = 6.21,2.57 Hz, 1 H) 7.37 (ddd, J = 8.94, 4.23, 2.64 Hz, 1 H) 7.13 (t, J = 8.72Hz, 1 H) 5.14 (d, J = 15.81 Hz, 1 H) 4.95-5.01 (m, 1 H) 4.47 (d, J =15.81 Hz, 1 H) 3.07 (dd, J = 15.81, 5.77 Hz, 1 H) 2.71 (d, J = 15.81 Hz,1 H) 1.23 (d, J = 6.78 Hz, 3H) 919 (E2) LCMS (M + 1): 436.1 920 (E1)LCMS (M + 1): 436,438

920 (E2) LCMS (M + 1): 436.0 ¹H NMR (400 MHz, Methanol-d₄) ppm 9.08 (s,1 H) 7.82 (d, J = 1.76 Hz, 1 H) 7.34-7.48 (m, 2 H) 7.02-7.09 (m, 1 H)5.16 (d, J = 15.81 Hz, 1 H) 4.95- 5.01 (m, 1 H) 4.50 (d, J = 15.81 Hz, 1H) 3.04-3.15 (m, 1 H) 2.72 (d, J = 15.81 Hz, 1 H) 1.25 (d, J = 6.78 Hz,3 H)

921 (E1) LCMS: 437/439 [M + 1]. 921 (E2) LCMS: 437/439 [M + 1].

922 (E1) LCMS: 383 [M + 1]. 922 (E2) LCMS: 383 [M + 1].

923 (E1) 1H NMR (400 MHz, METHANOL-d4) δ = 9.11 (d, J = 1.9 Hz, 1 H),7.86 (d, J = 2.0 Hz, 1 H), 7.24 (s, 1 H), 7.14-7.22 (m, 2 H), 6.88 (d, J= 6.9 Hz, 1H), 5.16 (d, J = 15.7 Hz, 1 H), 4.98-5.06 (m, 1 H), 4.49 (d,J = 15.7 Hz, 1 H), 3.09 (dd, J = 5.7, 15.7 Hz, 1 H), 2.73 (d, J = 15.9Hz, 1 H), 2.33 (s, 3 H), 1.25 (d, J = 6.8 Hz, 3 H). LCMS: 354 [M + 1].923 (E2) LCMS: 354 [M + 1].

924 (E1) 1H NMR (400 MHz, METHANOL-d4) δ = 9.10 (d, J = 1.6 Hz, 1 H),7.85 (d, J = 1.8 Hz, 1 H), 7.16-7.30 (m, 2 H), 6.95 (t, J = 9.2 Hz, 1H), 5.15 (d, J = 15.7 Hz, 1 H), 5.00 (quin, J = 6.4 Hz, 1 H), 4.47 (d, J= 15.7 Hz, 1 H), 3.08 (dd, J = 5.8, 15.8 Hz, 1 H), 2.72 (d, J = 15.8 Hz,1 H), 2.25 (d, J = 1.3 Hz, 3 H), 1.24 (d, J = 6.8 Hz, 3 H). LCMS: 372[M + 1]. 924 (E2) 1H NMR (400 MHz, METHANOL-d4) δ = 9.11 (d, J = 1.8 Hz,1 H), 7.85 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 2.4, 6.9 Hz, 1 H),7.16-7.22 (m, 1 H), 6.96 (t, J = 9.1 Hz, 1 H), 5.15 (d, J = 15.6 Hz, 1H), 5.01 (quin, J = 6.4 Hz, 1 H), 4.48 (d, J = 15.7 Hz, 1 H), 3.08 (dd,J = 6.0, 15.7 Hz, 1 H), 2.72 (d, J = 15.8 Hz, 1 H), 2.26 (d, J = 1.9 Hz,3 H), 1.25 (d, J = 6.9 Hz, 3 H). LCMS: 372 [M + 1].

Example 61: Preparation of Compound 289

Step 1: Preparation of Compound 3

To a solution of[5-tert-butoxycarbonyl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]boronicacid (300.00 mg, 755.00 umol, 1.00 eq) and 2-chloropyrimidine (129.71mg, 1.13 mmol, 1.50 eq) in dioxane (2.00 mL) was added Pd₂(dba)₃ (69.14mg, 75.50 umol, 0.10 eq), xphos (71.98 mg, 151.00 umol, 0.20 eq)followed by a solution of Na₂CO₃ (240.07 mg, 2.27 mmol, 3.00 eq) in H2O(400.00 uL). The mixture was heated to 90° C. for 16 h. The mixture wasextratced with EA (50 mL*2) and H₂O (10 mL). The combined organic layerwas dried over Na₂SO₄, and filtrated. The filtrate was concentrated invacuum. The residue was purified by falsh chromatography (PE:EA: 0%˜30%)to get 220 mg product with 30% purity. The product was purified byprep-HPLC (FA) to afford tert-butyl3-pyrimidin-2-yl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(46.50 mg, 107.74 umol, 14.27% yield) as colorless oil. LCMS(M+1): 432.

Preparation of Compound 289

Tert-butyl3-pyrimidin-2-yl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(60.00 mg, 139.02 umol, 1.00 eq) was dissolved in TFA (54.03 mmol, 4.00mL, 388.62 eq) and stirred at 20° C. for 16 hr. The mixture wasconentrated in vacuum to afford3-pyrimidin-2-yl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (44.00mg, crude, TFA) as yellow oil.

To a solution of3-pyrimidin-2-yl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (30.00mg, 95.16 umol, 1.00 eq, TFA) and phenyl N-(3-chlorophenyl) carbamate(18.86 mg, 76.13 umol, 0.80 eq) in DCM (4.00 mL) was added TEA (48.15mg, 475.80 umol, 65.96 uL, 5.00 eq). The mixture was stirred at 20° C.for 16 hr. The mixture was concentrated in vacuum. The residue waspurified by prep-HPLC (FA) to affordN-(3-chlorophenyl)-3-pyrimidin-2-yl-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxamide (22.39 mg, 62.60 umol, 65.79% yield, 99.2%purity) as white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.86-8.97 (m,3H), 7.64 (s, 1H), 7.41 (d, J=5.8 Hz, 2H), 7.26 (t, J=8.1 Hz, 1H),6.94-7.02 (m, 1H), 4.83 (brs, 2H), 3.78 (brs, 2H), 2.79 (brs, 2H). LCMS:355 [M+1].

Example 62: Preparation of Compound 290

Step 1: Preparation of Compound 3

To a solution of[5-tert-butoxycarbonyl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]boronicacid (300.00 mg, 755.00 umol, 1.00 eq and 3-chloropyridazine (129.71 mg,1.13 mmol, 1.50 eq) in dioxane (8.00 mL) was added Pd₂(dba)₃ (69.14 mg,75.50 umol, 0.10 eq), XPhos (71.98 mg, 151.00 umol, 0.20 eq) followed bya solution of Na₂CO₃ (240.07 mg, 2.27 mmol, 3.00 eq) in H₂O (2.00 mL).The mixture was heated to 85° C. for 16 hr. The mixture was extractedwith EA (50 mL*2) and H₂O (20 mL). The combined organic layer was driedover Na₂SO₄, and filtrated. The filtrate was concentrated in vacuum. Theresidue was purified by column chromatography (PE:EA=20%-50%) to affordtert-butyl3-pyridazin-3-yl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(75.00 mg, 147.71 umol, 19.56% yield, 85% purity) as yellow oil.LCMS(M+1): 432.

Preparation of Compound 290

Tert-butyl-3-pyridazin-3-yl-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(75.00 mg, 137.46 umol, 1.00 eq, TFA) was dissolved in TFA (6.85 g,60.09 mmol, 4.45 mL, 437.19 eq) and stirred at 20° C. for 16 hr. Themixture was concentrated in vacuum to afford3-pyridazin-3-yl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (59.00mg, crude, TFA) as yellow oil.

To a solution of3-pyridazin-3-yl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (59.00mg, 187.15 umol, 1.00 eq, TFA) in DCM (4.00 mL) was added phenylN-(3-chlorophenyl)carbamate (46.35 mg, 187.15 umol, 1.00 eq) followed byTEA (94.69 mg, 935.75 umol, 129.71 uL, 5.00 eq). The mixture was stirredat 20° C. for 16 hr. LCMS showed that compound 3 remained. Another batchof phenyl N-(3-chlorophenyl)carbamate (30 mg) was added. The mixture wasstirred at 20° C. for another 16 hr. The mixture was concentrated invacuum. LCMS showed 30% desired product. The residue was purified byprep-HPLC (FA) to affordN-(3-chlorophenyl)-3-pyridazin-3-yl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide(25.00 mg, 70.32 umol, 37.58% yield, 99.8% purity) as white solid.

¹H NMR (400 MHz, METHANOL-d4) δ ppm 2.93 (t, J=5.71 Hz, 2H) 3.90 (t,J=5.71 Hz, 2H) 5.00 (s, 2H) 6.99-7.04 (m, 1H) 7.21-7.29 (m, 1H)7.31-7.37 (m, 1H) 7.56 (t, J=2.01 Hz, 1H) 7.77 (dd, J=8.41, 4.77 Hz, 1H)8.28 (d, J=8.91 Hz, 1H) 9.11 (d, J=4.64 Hz, 1H). LCMS: 355 [M+1].

Example 63: HBV Assembly Assay

The interference of compounds from this invention with HBV capsidassembly could be measured using an in vitro assembly assay based onfluorescence quenching, which was developed according to a methoddescribed by Zlotnick and coworkers (Nature Biotechnology 2006, 24:358).In a typical assay, a mutant HBV C₁₅₀ protein (amino acids 1-150, C49A,C61A, C107A, 150C) is cloned into a T7 RNA-polymerase based expressionvector, expressed in E. coli and purified to homogeneity as a dimer. Thepurified HBV core protein is desalted and labeled with BODIPY-FL Dye.

In a non-limiting embodiment, the assembly assay is conducted in 96-wellplate format. The assembly reactions are carried out in 50 mM Hepesbuffer, pH 7.5 and 150 mM NaCl. The compounds are pre-incubated with theHBV CA protein for 15 min, and the assembly reactions are initiated byaddition of NaCl. The reaction is allowed to continue for 1 hour at roomtemperature. The changes in fluorescence between DMSO treated andcompound treated samples are recorded and analyzed for assemblymodulation.

Example 64: HBV Replication Inhibition Assay

HBV replication inhibition by the compounds of this invention could bedetermined in cells infected or transfected with HBV, or cells withstably integrated HBV, such as HepG2.2.15 cells (Sells et al. 1987). Inthis example, HepG2.2.15 cells were maintained in cell culture mediumcontaining 10% fetal bovine serum (FBS), Geneticin, L-glutamine,penicillin and streptomycin. HepG2.2.15 cells could be seeded in 96-wellplates at a density of 40,000 cells/well and be treated with seriallydiluted compounds at a final DMSO concentration of 0.5% either alone orin combination by adding drugs in a checker box format. Cells wereincubated with compounds for three days, after which medium was removedand fresh medium containing compounds was added to cells and incubatedfor another three days. At day 6, supernatant was removed and treatedwith DNase at 37° C. for 60 minutes, followed by enzyme inactivation at75° C. for 15 minutes. Encapsidated HBV DNA was released from thevirions and covalently linked HBV polymerase by incubating in lysisbuffer (Affymetrix QS0010) containing 2.5 ag proteinase K at 50° C. for40 minutes. HBV DNA was denatured by addition of 0.2 M NaOH and detectedusing a branched DNA (BDNA) QuantiGene assay kit according tomanufacturer recommendation (Affymetrix). HBV DNA levels could also bequantified using qPCR, based on amplification of encapsidated HBV DNAextraction with QuickExtraction Solution (Epicentre Biotechnologies) andamplification of HBV DNA using HBV specific PCR probes that canhybridize to HBV DNA and a fluorescently labeled probe for quantitation.In addition, cell viability of HepG2.2.15 cells incubated with testcompounds alone or in combination was determined by using CellTitre-Gloreagent according to the manufacturer protocol (Promega). The meanbackground signal from wells containing only culture medium wassubtracted from all other samples, and percent inhibition at eachcompound concentration was calculated by normalizing to signals fromHepG2.2.15 cells treated with 0.5% DMSO using equation E1.

E1: % inhibition=(DMSOave−Xi)/DMSOave×100%

where DMSOave is the mean signal calculated from the wells that weretreated with DMSO control (0% inhibition control) and Xi is the signalmeasured from the individual wells. EC50 values, effectiveconcentrations that achieved 50% inhibitory effect, were determined bynon-linear fitting using Graphpad Prism software (San Diego, Calif.) andequation E2

E2: Y=Ymin+(Ymax−Ymin)/(1+10(Log EC50-X)×HillSlope)

where Y represents percent inhibition values and X represents thelogarithm of compound concentrations.

Selected compounds of the invention were assayed in the HBV replicationassay (BDNA assay), as described above and a representative group ofthese active compounds is shown in Table 3. In Table 3, “A” represents0.01<EC₅₀<0.10; “B” represents 0.10≤EC₅₀<0.50; “C” represents0.50≤EC₅₀<1.0; “D” represents 1.0≤EC₅₀<1.5; and “E” represents1.5≤EC₅₀<5.

TABLE 3 Activity in BDNA-assay: ‘+’ indicates >50% activity at 10 μM, ornumerical value indicates EC50 (μM). Compound Activity Compound Activity001 + 318(E1) B 014 D 318(E2) B 017 + 325 + 016 + 326 B 021 + 327 B 022B 436 C 024 + 027 + 472 B 030 + 473 C 057 + 495 D 112 A 496 B 114 A 497B 113 + 542 C 142 + 555 B 143 + 556 B 144 + 559 A 145 + 560 A 147 + 562A 148 + 583 E 149 + 917 E1 A 150 + 917 E2 A 154 + 918 E1 A 156 + 918 E2A 163 + 919 E1 A 164 + 919 E2 A 165 + 920 E1 A 171 + 920 E2 A 190 C 921E1 A 191 C 921 E2 A 192 B 922 E1 A 201 + 922 E2 A 204 + 923 E1 A 205 B923 E2 A 214 + 924 E1 A 226 + 924 E2 A 276 B 289 A 277 + 290 A 278 B 279B 280 B 281 + 286 C 287 B 291 B 317 (E1) A 317(E2) B

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety.

While the invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention. The appendedclaims are intended to be construed to include all such embodiments andequivalent variations.

1. A compound of Formula II

or a pharmaceutically acceptable salt thereof, wherein Y is selectedfrom —C(O)— and —SO₂—; Z is selected from —(CR⁵R⁶)_(m)—,—(CR⁵R⁶)_(m)CR⁵═CR⁵—, and —(CR⁵R⁶)_(m)—C₃-C₆-cycloalkylene; R¹ isC₆-aryl; R² is, at each occurrence, independently selected from H, —OH,halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;R³ is, at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁴ isC₆-aryl; R⁵ is, at each occurrence, independently selected from H, —OH,halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;alternatively, R⁴ and R⁵ are optionally joined to form a heterocyclicring; R⁶ is, at each occurrence, independently selected from H, —OH,halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;m is 0, 1, 2, 3, or 4; and n is 0, 1, 2, or
 3. 2-5. (canceled)
 6. Thecompound of claim 1, wherein Z is —(CR⁵R⁶)_(m).
 7. The compound of claim1, wherein m is 0 or 1; R⁵ is H, —OH, or C₁-C₆-alkyl; and R⁶ is H orC₁-C₆-alkyl.
 8. (canceled)
 9. (canceled)
 10. The compound of claim 1,wherein R² is H, C₁-C₆-alkyl, or C₁-C₆-alkyl-OH and R³ is H orC₁-C₆-alkyl. 11-13. (canceled)
 14. The compound of claim 1, wherein nis
 1. 15-21. (canceled)
 22. The compound of claim 1, wherein R² is H,C₁-C₆-alkyl, or C₁-C₆-alkyl-OH; R³ is H or C₁-C₆-alkyl; and n is 1.23-27. (canceled)
 28. A compound of Formula IIIa:

or a pharmaceutically acceptable salt thereof, wherein Y is —C(O)— or—SO₂—; R¹ is C₁-C₉-heteroaryl which is optionally substituted with 1 or2 groups each independently selected from —OH, halo, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, CN, and C(O)H; R² is,at each occurrence, independently selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R³ isselected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁴ is (CR⁸R⁹)_(p)—C₆-C₁₂-aryl,optionally substituted with 1, 2, or 3 groups, each independentlyselected from —OH, halo, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁷ is selected from H, C₁-C₆-alkyl,and C₁-C₆-alkyl-OH; R⁸ is, at each occurrence, independently selectedfrom H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, andC₁-C₆-alkyl-OH; R⁹ is, at each occurrence, independently selected from Hand C₁-C₆-alkyl; and p is 0, 1, 2, 3, or
 4. 29. The compound of claim28, wherein Y is —C(O)—.
 30. The compound of claim 28, wherein R¹ ispyrimidyl, pyridyl, pyrazolyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, pyridazinyl, pyrazinyl, or pyrrolyl, any of which areoptionally substituted by 1 or 2 groups independently selected from —OH,halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, CN,and C(O)H.
 31. (canceled)
 32. The compound of claim 28, wherein R² is H,C₁-C₆-alkyl, or C₁-C₆-alkyl-OH and R³ is H or C₁-C₆-alkyl.
 33. Thecompound of claim 28, wherein R⁴ is (CR⁸R⁹)_(p)—C₆-aryl, which isoptionally substituted with 1, 2, or 3 groups, each independentlyselected from —OH, halo, CN, and C₁-C₆-alkyl; R⁸ is H or C₁-C₆-alkyl; R⁹is H or C₁-C₆-alkyl; and p is 0 or
 1. 34. (canceled)
 35. The compound ofclaim 28, wherein R⁴ is:

36-41. (canceled)
 42. The compound of claim 1, wherein the compound isselected from

and pharmaceutically acceptable salts thereof.
 43. (canceled)
 44. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier. 45-54. (canceled)
 55. The compoundof claim 28, wherein the compound of Formula Illa is selected from thegroup consisting of:

and pharmaceutically acceptable salts thereof.
 56. The compound of claim28, wherein: Y is —C(O)—; R² is, at each occurrence, H; R³ is H; R⁴ isphenyl substituted with 2 or 3 substituents, each independently selectedfrom the group consisting of —OH, halo, CN, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; and R⁷ is H. 57.The compound of claim 56, wherein R¹ is thienyl optionally substitutedwith halo, C₁-C₆-alkyl, C₁-C₆-alkyl-OH or CN.
 58. The compound of claim56, wherein R⁴ is substituted with 1, 2 or 3 substituents, eachindependently selected from the group consisting of halo, methyl and CN.59. The compound of claim 56, wherein the compound of Formula IIIa isselected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 60. A pharmaceuticalcomposition comprising a compound of claim 28, or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablecarrier.
 61. A compound of Formula IIIb:

or a pharmaceutically acceptable salt thereof, wherein Y is —C(O)— or—SO₂—; R¹ is C₆-C₁₂-aryl; R² is, at each occurrence, independentlyselected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R³ is selected from H, —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁴ isselected from (CR⁸R⁹)_(p)—C₁-C₉-heteroaryl and (CR⁸R⁹)_(p)—C₆-C₁₂-aryl,wherein heteroaryl and aryl are optionally substituted with 2 or 3groups, each independently selected from —OH, halo, CN, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁷ is selected fromH, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁸ is, at each occurrence,independently selected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁹ is, at each occurrence,independently selected from H and C₁-C₆-alkyl; and p is 0, 1, 2, 3, or4.
 62. The compound of claim 61, wherein Y is —C(O)—.
 63. The compoundof claim 61, wherein R¹ is phenyl.
 64. The compound of claim 61, whereinR² is H.
 65. The compound of claim 61, wherein R⁴ is:


66. The compound of claim 61, wherein R⁷ is H.
 67. The compound of claim61, wherein the compound of Formula IIIb is selected from the groupconsisting of:

and pharmaceutically acceptable salts thereof.
 68. The compound of claim61, wherein Y is —C(O)—; R¹ is phenyl; R² is, at each occurrence, H; R³is H; R⁴ is phenyl substituted with 2 or 3 substituents, eachindependently selected from the group consisting of —OH, halo, CN,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; and R⁷is H.
 69. The compound of claim 68, wherein R⁴ is substituted with 2 or3 substituents, each independently selected from the group consisting ofhalo, methyl and CN.
 70. The compound of claim 68, wherein the compoundof Formula IIIb is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 71. A pharmaceuticalcomposition comprising a compound of claim 61, or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablecarrier.
 72. A compound of Formula IIIc:

or a pharmaceutically acceptable salt thereof, wherein Y is —C(O)— or—SO₂—; R¹ is C₆-C₁₂-aryl substituted with 1 or 2 groups eachindependently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, CN, and C(O)H; R² is, at eachoccurrence, independently selected from H, —OH, halo, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R³ is selected fromH, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, andC₁-C₆-alkyl-OH; R⁴ is (CR⁸R⁹)_(p)—C₆-C₁₂-aryl substituted with 1, 2, or3 groups, each independently selected from —OH, halo, CN, C₁-C₆-alkyl,C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁷ is selected fromH, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁸ is, at each occurrence,independently selected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl,—O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH; R⁹ is, at each occurrence,independently selected from H and C₁-C₆-alkyl; and p is 0, 1, 2, 3, or4.
 73. The compound of claim 72, wherein Y is —C(O)—.
 74. The compoundof claim 72, wherein R¹ is phenyl substituted with —OH, halo,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, C₁-C₆-alkyl-OH, CN, andC(O)H.
 75. The compound of claim 72, wherein R² is H.
 76. The compoundof claim 72, wherein R⁴ is phenyl substituted with —OH, halo, CN,C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. 77.The compound of claim 72, wherein the compound of Formula IIIc isselected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 78. A pharmaceuticalcomposition comprising a compound of claim 72, or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablecarrier.